Targeting angiogenesis in diabetic wound healing: New insight from chemical architecture to functional outcomes

Abstract

Diabetic wound healing (DWH) is a multifaceted process hindered by impaired angiogenesis that usually leads to increased risks of infection and amputation. Targeting impeded angiogenic signals to restore the microenvironment favoring vascular network re-establishment is a promising therapeutic strategy for diabetic wound. Natural products have emerged as potential therapeutic agents for diabetic wounds by regulating endotheliocytes functions and their cross-talks with immune cells and fibroblasts, while the similarities and differences of the chemical structures greatly determine their distinct efficient and underlying mechanisms in diabetic wound angiogenesis. In this review, relevant literature was retrieved from PubMed, Google Scholar, and Web of Science databases, covering publications from 2020 to 2025. This paper reviews the role of angiogenesis in DWH and the action of natural products in DWH by targeting angiogenesis, particularly highlighting their chemical architecture driven specific biological activity on angiogenesis, with the aim of providing references for angiogenesis-based therapeutic strategies for diabetic ulcers and promoting the development of angiogenesis-targeting agents.

Graphical abstract

Highlights

• •Natural products exhibit powerful effect in diabetic wound healing by targeting angiogenesis.
• •Chemical architecture of natural products drives specific biological activity on angiogenesis.
• •Structural features of natural products guide development of angiogenesis-targeting agents.

1. Introduction

Diabetic foot ulcer (DFU) is one of the most severe complications of diabetes mellitus (DM) and approximately one third of people with type 1 or type 2 DM will suffer a foot ulcer in their lifetime [1]. It is estimated that about 18.6 million diabetic patients develop a foot ulcer every year around the world, and more importantly, if inadequately treated, DFU can advance to soft tissue infection, gangrene and limb loss [2]. The 5-year mortality rate of patients with DFU is about 30%, while the mortality rate for patients with above-ground foot amputations exceeds 70%, which imposes a considerable economic burden on patients and society [3]. Despite various strategies have been proposed to treat the diabetic wounds, including debridement, off-loading, wound dressing, and revascularization, etc. [4], the clinical management of the DFU remains extremely challenging.

Impaired angiogenesis is the central pathological feature of DFUs, and hyperglycemia in wound site leads to excessive production of reactive oxygen species (ROS) and advanced glycation end-products, which destabilize hypoxia-inducible factor-1α (HIF-1α) and suppress vascular endothelial growth factor (VEGF) expression, impairing endothelial cell (EC) function [5]. Similarly, sustained hyperglycemia and accumulated proinflammatory cytokines contribute to over-polarization of M1 macrophages [6] that activates nuclear factor-kappa B (NF-κB) signaling pathway and exacerbates inflammatory response at wound site, leading to the dysfunction of ECs and creating a hostile microenvironment for vascular repair [7]. In addition, the abnormal energy metabolism of ECs, keratinocytes, and macrophages as well as impaired extracellular matrix (ECM) remodeling triggered by DM also compromise wound angiogenesis [8,9]. Furthermore, non-coding RNAs (ncRNAs) have emerged as crucial regulators of gene expression, adding another layer of complexity to the angiogenic response in diabetic wound [10,11]. Given these challenges, therapeutic strategies that restore angiogenesis hold immense potential for improving diabetic wound healing (DWH) outcomes.

Natural products exhibit diverse bioactivities, involving antioxidant, anti-inflammatory, and pro-angiogenic effects, making them ideal candidates for addressing the multifaceted nature of diabetic wounds [12]. The pro-angiogenic efficacy of bioactives in DWH is largely dictated by their chemical structures, which modulate their bioavailability, target specificity, and interaction with angiogenic signaling pathways. Flavonoids like quercetin and epigallocatechin gallate (EGCG) have been shown to upregulate VEGF expression, enhance EC migration, and mitigate oxidative stress [13,14]. In addition, polyphenols such as resveratrol (RES) and curcumin not only stimulate angiogenic signaling pathways but also suppress chronic inflammation, creating a conducive environment for vascular repair [15]. Besides, a lot of polysaccharides and glycosides, including those derived from traditional medicinal herbs, promote macrophage polarization toward the M2 phenotype, supporting pro-angiogenic activity [16]. Interestingly, a portion of the natural products were able to promote neovascularization by modulating cross-talk between macrophages, ECs and other cell types at the wound site [17]. These compounds provide a natural, multi-targeted approach to counteracting the pathophysiological impairments in diabetic wounds (Table S1 [[18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55]]).

In this review, the literature published in PubMed, Google Scholar, and Web of Science in the past decade (2015–2025) were collected using the keywords including angiogenesis, DWH, ECs, and natural products. The initial search yielded approximately 745 articles. After screening based on thematic relevance, removal of duplicates, exclusion of non-English articles, conference abstracts, and studies lacking in vivo or in vitro experimental validation, as well as those with poor methodological quality or insufficient data support, a total of 125 original research articles were finally included in this review. Select publications published before 2015 were incorporated as they offer essential foundational insights into the discussed mechanisms. This paper focus on molecular mechanisms of neovascularization in DWH and the potential therapeutic mechanisms of angiogenesis-targeting natural products in diabetic wounds and how the chemical features of natural products drive their pro-angiogenic effects in DWH, aiming to provide a theoretical basis for angiogenesis-targeting therapies to promote DWH in clinic and to facilitate the development of angiogenesis-targeting natural products as drug candidates for DFU.

2. Natural products-based therapies target angiogenesis in DWH

2.1. ECs function

2.1.1. Molecular signals

HIF-1α can be regulated by growth differentiation factor 11 (GDF11) that is down-regulated in wound site of diabetic mice. Exogenous GDF11 increases granulation tissue, collagen (COL) deposition, and blood vessels, and promotes the migration and tube formation of epithelial progenitor cells (EPCs) via upregulating HIF-1α, VEGF, and stromal cell-derived factor 1α (SDF-1α) in human umbilical vein endothelial cells (HUVECs). However, the inhibitor of HIF-1α or siGDF11 abolishes the pro-angiogenesis effect of GDF11 [56]. Moreover, innate defense regulator (IDR) 1018 is a possible target to enhance DWH via regulating HIF-1α, which promotes angiogenesis in high glucose (HG)-treated ECs via upregulating VEGF, angiogenin gene (ANG), and transforming growth factor-beta (TGF-β) and downregulating HIF-1α under hypoxia [57]. The VEGF family of ligands primarily binds to two main receptors, vascular endothelial growth factor receptor1 (VEGFR1) and VEGFR2, both of which play distinct roles in angiogenesis. Placental growth factor (PlGF) is a critical VEGF family member that participated in DWH by regulating angiogenesis. PlGF accelerates wound closure in diabetic mice via improving angiogenesis and increasing macrophage numbers by upregulating VEGFR1 expression, whereas VEGFR1 loss in macrophage abolishes the positive effects of PIGF on DWH [58,59], which might be ascribed to decreased macrophage recruitment and reduced M2 polarization. VEGFR2 is the main receptor driving angiogenesis that initiates key signaling pathways for EC proliferation, migration, and survival. Up-regulated protein phosphotyrosine phosphatase 1B (PTP1B) attenuates wound healing in diabetic mice via decreasing VEGF and hampers the function of bovine aortic endothelial cells (BAECs) by suppressing phosphorylated-vascular endothelial growth factor receptor 2 (p-VEGFR2) and phosphorylated-protein kinase B (p-Akt), while these effects are abolished by the calpain activation or PTP1B knock-down [60]. Poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) is increased in diabetic mice and HG-induced in HUVECs and associated with delayed wound healing and suppressed migration of ECs. However, PARP inhibitor accelerates wound healing and migration of ECs via increasing VEGFR2 and endothelial nitric oxide synthase (eNOS) expressions [61].

Cluster of differentiation 31 (CD31) is a key marker of ECs that plays a significant part in angiogenesis, and restoring CD31 activity in diabetic conditions has therapeutic potential for chronic wound. CD93 is a transmembrane glycoprotein, which accelerates new vessels formation and re-epithelization via increasing the expression of CD31 in diabetic mice. Besides, it also promotes tube formation and sprouting abilities of human microvascular endothelial cell-1 (HMEC-1) via upregulating phosphorylated-p38 mitogen-activated protein kinases (p-p38) and phosphorylated-mitogen-activated protein kinases-activated protein kinase 2 (p-MK2) [62]. In addition, CD100 improves wound healing in db/db mice through promoting COL deposition, granulation formation, and angiogenesis and reducing inflammation via increasing the expression of COL I/III and CD31 and decreasing that of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) [63]. Neurokinin 1 receptor (NK1R) is increased in diabetic mice and associated with impaired angiogenesis, whereas NK1R inhibition accelerates wound healing through improving angiogenesis via downregulating CD31 and forkhead box p2 (FOXP2) [64]. Furthermore, serum derived exosomes (Serum-Exos) accelerate wound healing in diabetic mice by improving COL deposition and angiogenesis via augmenting the expression of fibronectin, COL-α, and CD31. Meanwhile, Serum-Exos also improve the migration and proliferation of NIH/3T3 cells and promote the tube formation of HUVECs [65].

2.1.2. Natural products target ECs functions

A number of natural products improve angiogenesis at diabetic wound sites through targeting HIF-1α signal. Hydroxysafflor yellow A (HSYA) is a valuable ingredient isolated from safflower with potent pro-angiogenic effects that improves wound angiogenesis in diabetic mice via elevating the levels of HIF-1α [18]. In addition, pterostilbene (PTE) is a naturally occurring polyphenolic compound that promotes wound healing in diabetic rats through restoring HIF1α activity and upregulating the content of VEGF [19]. Astragaloside IV (AS-IV), a bioactive constituent separated from Astragalus, has emerged as a promising agent for DWH [66]. AS-IV treatment reveres the decreased proliferation and migration of HUVECs induced by HG and facilities wound healing in diabetic rats through upregulating HIF-1α, peroxisome proliferative activated receptor gamma (PPARγ), and VEGFR2 [20]. Likewise, Asperosaponin VI (ASA VI) induces angiogenesis through HIF-1α/VEGF signaling, which promotes migration and tube formation of HG-treat HUVECs and facilities wound healing in diabetic rats by increasing re-epithelialization, granulation and COL formation, and upregulating HIF-1α and VEGF, while these effects are reversed by the inhibitor of HIF-1α [21].

Regulating the expression of VEGF and its receptor is another mechanism of natural products in improving angiogenic function of ECs during DWH. Hesperidin (hesperetin-7-rhamnoglucoside (HSP)) and curcumol promote wound neovascularization in diabetic animal models by upregulating VEGF, Vegfr1, and Vegfr2 [22,23]. In addition, cryptotanshinone (CTS), a diterpene quinone compound separated from Salvia miltiorrhiza Bge, accelerates wound healing in diabetic mice through promoting re-epithelialization, suppressing inflammation, and improving angiogenesis, as evidenced by the down-regulation of C−X−C motif ligand 1 (Cxcl1) and Cxcl2, increase of phosphorylated-endothelial nitric oxide synthase (p-eNOS), and elevation of VEGF and angiopoietin-1 (Ang-1). Furthermore, CTS intervention boosts tube formation and enhances VEGF expression in HUVECs [24]. Interestingly, topical application of luteolin increases new blood vessels and fibroblasts, accelerates re-epithelialization, facilitates COL deposition and orientation, but down-regulates VEGF in epithelialized wound [25].

Additionally, a portion of natural products could up-regulate the expression of CD31 that contributes to angiogenesis in diabetic wound. Snail glycosaminoglycan (SGAG), a polysaccharide derived from the China white jade snail, narrows the diameter of wounds in diabetic mice, attenuates inflammation, accelerates angiogenesis, and promotes increase of alpha-smooth muscle actin (α-SMA) and CD31 [26]. Mangiferin (MF) promotes migration of HUVECs under diabetic condition, facilitates tube formation, and upregulates the levels of platelet-derived growth factor (PDGF) and VEGF. Notably, MF accelerates wound healing in diabetic rats via reducing inflammatory cell infiltration, promoting COL deposition and neovascularization, and increasing capillary density, with the up-regulation of CD31 and α-SMA [27]. The molecular mechanisms of angiogenesis in diabetic wound and therapeutic effects of natural products are portrayed in Fig. 1. The chemical structures of natural products targeting angiogenic function of ECs in diabetic wound are shown in Fig. 2.

Fig. 1.

Molecular mechanisms of angiogenesis in diabetic wound and therapeutic effects of natural products. Vascular endothelial cells (ECs) proliferate and migrate toward the wound site to promote diabetic wound healing (DWH), which is regulated by multiple signaling pathways, especially those centered on hypoxia-inducible factor-1α (HIF-1α), nuclear factor-kappa B (NF-κB), and tumor protein 53 (p53). In addition, macrophages and keratinocytes regulate diabetic wound neovascularization through paracrine pathways. Natural products promote angiogenesis in diabetic wound principally through activating HIF-1α/vascular endothelial growth factor (VEGF) signals in ECs. PARP: poly-adenosine diphosphate-ribose polymerase; p-eNOS: phosphorylated-endothelial nitric oxide synthase; PI3K: phosphoinositide 3-kinase; Akt: protein kinase B; CTS: cryptotanshinone; PTP1B: protein phosphotyrosine phosphatase 1B; VEGFR: vascular endothelial growth factor receptor; ROS: reactive oxygen species; Siah1/2: siah E3 ubiquitin protein ligase 1/2; FasL: factor-related apoptosis ligand; ERK: extracellular signal-regulated kinase; PHD: prolyl hydroxylase domain-containing protein; PKA: protein kinase A; SGAG: snail glycosaminoglycan; PTE: pterostilbene; HSYA: hydroxysafflor yellow A; ICER: inducible cyclic adenosine monophosphate early repressor; CER: cyclic adenosine monophosphate early repressor; GDF: growth differentiation factor; ASA VI: Asperosaponin VI; AS-IV: astragaloside IV; PGT: prostaglandin transporter; PAI-1: plasminogen activator inhibitor-1; NK1R: neurokinin 1 receptor; PGE₂: prostaglandin E2; MDA: malondialdehyde; HO-1: heme oxygenase-1; ICAM-1: intercellular cell adhesion molecule-1; SOD: superoxide dismutase; MGF-E8: milk fat globule endothelial growth factor 8; IL: interleukin; CCL: C-C motif chemokine ligand; CREB: cyclic adenosine monophosphate response element binding protein; PlGF: placental growth factor; DAD₁R: dopamine D₁ receptor.

Fig. 2.

Chemical structures of natural products targeting angiogenic function of endothelial cells (ECs), inflammatory response, and energy metabolism in diabetic wound.

2.2. Inflammatory response

2.2.1. Molecular signals

DNA methyltransferase 1 (DNMT1)/Ang-1/NF-κB axis is associated with impaired angiogenesis in diabetic wound. DNMT1 inhibition ameliorates decreased angiogenesis and aggravated inflammation in wound site of diabetic mice, with the decrease of IL-1β, TNF-α, intercellular cell adhesion molecule-1 (ICAM-1), DNMT1, and phosphorylated-nuclear factor-kappa B p65 subunit (p-p65). Meanwhile, increased inflammation in HG-treated ECs is also attenuated by recombinant Ang-1 or DNMT1 inhibitor [67]. Elabela, the ligand of apelin receptor (APJ), promotes wound closure in diabetic mice through reducing inflammation and DNA damage and facilitating angiogenesis via decreasing IL-6, TNF-α, 8-hydroxyguanosine (8-OHDG), TNF receptor associated factor 1 (TRAF1), and p-p65. Besides, elabela also suppresses HG and TRAF1-overexpression induced the DNA-damage and alleviates the autophagy in HUVECs, while APJ-siRNA reverses these effects of elabela and exacerbates the DNA damage via increasing the TRAF1, phosphorylated-inhibitor of nuclear factor-kappa B alpha (p-IκBα), and p-p65 [68]. CXCL5 is increased in EPCs from diabetic patients and mice, while its neutralizing antibody improves angiogenesis via upregulating VEGF and SDF-1. Compared with the streptozotocin (STZ)-treated mice, wound healing rate and blood vessel density are increased in the STZ-treated CXCL5 KO mice. Besides, increased CXCL5 in human aortic endothelial cells (HAECs) upregulates the expression of p-extracellular signal-regulated kinase (ERK), p65 and the levels of inflammatory cytokines and downregulates the expression of VEGF and SDF-1, whereas the inhibitors of ERK and C−X−C motif chemokine receptor (CXCR2) reverse these effects of CXCL5 [69], indicating that CXCL5 retards angiogenesis through activating ERK/p65 pathway via CXCR2. Interfering with the down-stream signals associated with NF-κB especially inflammatory cytokines contributes to angiogenesis in DWH. As a ligand for chemokine receptor C-C motif chemokine receptor 10 (CCR10) chemokine, C-C motif chemokine ligand 28 (CCL28) is elevated in tissues from diabetic patients and diabetic mice that decreases angiogenesis by elevating IL-1β, IL-6, TNF-α, and CCR10 and reducing eNOS. However, CCL28 suppression facilitates DWH in db/db mice via decreasing pro-inflammatory mediators and improving IL-4, eNOS, nitric oxide (NO), and VEGF [70]. Taken together, these findings suggested that suppressing CCL28-triggered inflammation might be a therapeutic strategy to improve wound angiogenesis in DM.

Signal transducer and activator of transcription (STAT) signaling pathway, particularly STAT3, plays a critical role in regulating diabetic wound angiogenesis. IL-10 overexpression accelerates wound healing in db/db mice by improving re-epithelialization and angiogenesis through recruiting the EPCs and increasing TGF-β3, VEGF, CXCL12, and CXCR4, whereas these effects are abolished in STAT3^−/− mice [71]. STAT6 signal drives alternative macrophage polarization that secretes pro-angiogenic factors for vascular regeneration. STAT6 activation also promotes PPARγ in macrophages, boosting VEGF secretion, and PPARγ ligands can amplify STAT6-mediated M2 polarization, creating a positive feedback loop for angiogenesis [72]. P311, relevant to the regeneration of neurons in mice, could increase DWH by promoting M2 macrophages polarization via mediating mechanistic target of rapamycin (mTOR)/IL-4R/STAT6 signaling pathway. P311 deficiency prolongs wound healing in mice through protracting inflammation and suppressing the angiogenesis. Besides, the expressions of M2 macrophage markers are decreased in P311^−/− wound macrophages and bone marrow-derived macrophages (BMDMs), with reduced IL-10 and TGF-β and VEGF and increased CD86 and TNF-α. The loss of P311 inhibits the levels of mTOR, IL-4R, and p-STAT6 in BMDMs, whereas recover P311 reverses these changes in P311^−/− macrophages. In addition, mTOR inhibitor restrains the IL-4R/STAT6 signaling pathway and the M2 polarization of macrophages [73,74]. Silencing progestin and adipoQ receptor 3 (PAQR3) accelerates wound healing in db/db mice through promoting angiogenesis and activating M2 macrophages via increasing arginase-1 (Arg-1), IL-10, mannose receptor C type 1 (Mrc-1), and PPARα/γ and decreasing inducible nitric oxide synthase (iNOS) and IL-12, and suppresses the M1-to-M2 macrophages polarization in vitro via inhibiting the stress induced phosphoprotein 1 (STIP1) homology and U-box-containing protein 1 (STUB1)-induced PPARγ ubiquitination and degradation. Moreover, PAQR3 silence in M2 macrophages also contributes to improved migration of human immortalized keratinocyte cell line (HaCaT) and tube formation of HUVECs [75].

2.2.2. Natural products target inflammatory response

Suppressing the activation of NF-κB signal to alleviate inflammatory response is a pivotal mechanism of natural products in improving diabetic wound angiogenesis. luteolin, icariin, kirenol, and vicenin-2 significantly accelerate wound closure in diabetic rats through promoting neovascularization, enhancing COL deposition, and inhibiting inflammation, with the down-regulation of NF-κB, matrix metalloproteinases 9 (MMP-9), TNF-α, IL-6, and IL-1β [25,[28], [29], [30]]. In addition, lupeol is a triterpene found in the stem bark of Bowdichia virgilioides, which reduces inflammatory cells, increases the expression of TNF-α, heme oxygenase-1 (HO-1), superoxide dismutase-2 (SOD-2), and IL-10 and decreases the levels of Nfκb, IL-6, and IL-1β [31]. Neferine, a dibenzylisoquino-line alkaloid separated from lotus seed, promotes wound closure of diabetic rats, improves the production of thicker granulation tissue and neovascularization, and accelerates epithelialization through promoting the secretion of insulin and downregulating NF-κB, TNF-α, IL-6, and IL-1β [32]. In addition, modulating macrophage polarization to provide an angiogenesis favorable environment is another mechanism of natural products in improving diabetic wound. Curcumin promotes granulation tissue formation, re-epithelialization, and neovascularization in wound sites of diabetic mice by upregulating Nfκb at day 7 post-wounding and shifting macrophages polarization towards M2 phenotype [33]. In addition, several natural products-based advanced formulations, such as dual-cross-linked methacryloyl-substituted bletilla striata polysaccharide (BSP) and gelatin hydrogel patch [76], morphologically switchable Au nanowire and hemoglobin-RES nanoparticles microneedle [77], paeoniflorin (PF)-loaded hyaluronic acid-based hydrogel [78], and SGAG/methacrylated gelatin hydrogel [79], could accelerate angiogenesis in diabetic wound through regulating the polarization of macrophages from M1 to M2 phenotype. These delivery systems often demonstrate superior therapeutic efficacy compared to natural products alone. The chemical structures of natural products targeting inflammation in diabetic wound angiogenesis are shown in Fig. 2. The molecular mechanisms of inflammation in diabetic wound angiogenesis and therapeutic effects of natural products are displayed in Fig. 3.

Fig. 3.

Molecular mechanisms of inflammation in diabetic wound angiogenesis and therapeutic effects of natural products. The polarization of macrophages largely determines the fate of vascular endothelial cells (ECs) and keratinocytes in diabetic wounds. Typically, high glucose (HG) induces the activation of nuclear factor-kappa B (NF-κB) signaling pathway, which contributes to the accumulation of pro-inflammatory mediators that hinder the activation of M2 macrophages (with the suppression of signal transducer and activator of transcription (STAT)-6 and peroxisome proliferative activated receptor gamma (PPARγ) and the angiogenic function of ECs, thereby resulting in delayed wound healing. Natural products suppress inflammatory response in diabetic wounds primarily by modulating M1/M2 macrophages polarization, thereby restoring a pro-angiogenic microenvironment and promoting diabetic wound healing (DWH). CCL: C−C motif chemokine ligand; IL: interleukin; DM: diabetes mellitus; CCR: C-C motif chemokine receptor; TNF-α: tumor necrosis factor α; EPCs: epithelial progenitor cells; Mϕ: macrophage; ELA: elabela; APJ: apelin receptor; CXCL: C−X−C motif chemokine ligand; CXCR: C−X−C motif chemokine receptor; ERK: extracellular signal-regulated kinase; EETs: epoxyeicosatrienoic acids; p53: tumor protein 53; CYP: cytochrome P450; PEDF: pigment epithelium-derived factor; MMP: matrix metalloproteinase; DNMT1: DNA Methyltransferase 1; Ang-1: angiopoietin-1; NO: nitric oxide; VEGF: vascular endothelial growth factor; TGF: transforming growth factor; iNOS: inducible nitric oxide synthase; ANGPTL4: angiopoietin like 4; JAK: Janus kinase; mTOR: mechanistic target of rapamycin; VEGF: Vascular endothelial growth factor; Arg-1: arginase-1; PAQR3: progestin and adipoQ receptor 3.

2.3. Energy metabolism

2.3.1. Molecular signals

Diabetic wounds often exhibit mitochondrial dysfunction and reduced energy production, which compromise the cellular activities required for angiogenesis in wound healing. Akt signals influences energy metabolism by regulating glycolysis and oxidative phosphorylation and promoting lipid and glucose metabolism, while impaired Akt signaling in diabetic wounds causes reduced angiogenesis [80], thus targeting Akt-mediated signaling pathways is a promising strategy for delayed wound healing in DM.

Akt/Girdin signaling pathway is relevant to angiogenesis during DWH. HG increases Na⁺/H⁺ exchanger 1 (NHE1) and reduces p-Akt and p-girdin in HUVECs that results in endothelial dysfunction, whereas NHE1 inhibition and Akt overexpression abolish these phenomena induced by HG. Meanwhile, NHE1 inhibition also reverses impaired angiogenesis in STZ-induced hind limb ischemia mouse by increasing the p-Akt and p-girdin [81]. Additionally, impaired angiogenesis in diabetic wound is associated with dysregulation of sirtuin1 (SIRT1)/Akt/nuclear factor erythroid 2-related factor-2 (Nrf-2) signal in ECs. SIRT1 is decreased in skin tissues from diabetic patients and mice, whereas SIRT1 activator accelerates wound healing via improving angiogenesis. Besides, SIRT1 promotes tube formation of HUVECs and suppresses oxidative stress via upregulating the expression of p-Akt [82]. S1P is a lipid synthesized by sphingosine kinase 1/2 (SPK1/2), which facilitates wound healing in diabetic mice by facilitating angiogenesis, but knockdown of S1P receptor1 (S1PR1) inhibits wound repair. Besides, S1P improves angiogenic function of HG-treated HUVECs, with elevated levels of p-Akt and VEGF-A, whereas these effects are offset by shS1PR1. Importantly, p-Akt inhibitor abolishes the effects of S1PR1 [83], which indicates that S1P promoted the angiogenic function of ECs via modulating Akt/FN1/VEGF-A axis. Leucine-rich α-2-glycoprotein 1 (LRG1) is a glycoprotein from bone marrow derived cells associated with inflammatory response, which is increased in diabetic mice and ulcer tissues of DFU patients. Overexpression of LRG1 impairs wound healing in diabetic mice by reducing the neutrophil extracellular traps (NETosis), whereas LRG1 deletion accelerates diabetic wound angiogenesis. Notably, inhibitors of Akt and type I receptor activin-like kinase 5 (ALK5) attenuate LRG1 induced increase of H3Cit and activation of Akt in dHL-60 cells [84], which reveals that mediating LRG1/ALK5/Αkt signaling pathway might be a novel strategy for angiogenesis in diabetic wound. Meteorin-like (Metrnl) is a secreted protein that affects the ECs proliferation and migration thereby mediating angiogenesis and COL deposition in wound closure. Metrnl^−/− mice and EC-Metrnl^−/− mice exhibit delayed wound healing and Metrnl knockdown suppresses the angiogenic functions of HUVECs and down-regulates the expression of p-eNOS, p-Akt, and VEGF-A [85]. Moreover, Metrnl facilitates wound healing in diabetic mice by accelerating re-epithelization, angiogenesis, and COL deposition, and enhances migration and proliferation of keratinocytes, while knockdown of Metrnl displays opposite effects. In addition, Metrnl up-regulates c-Kit and p-Akt in HUVECs and HaCaT cells, whereas inhibition of Kit abolishes the effect of Metrnl and inhibits tube formation of HUVECs [86]. Altogether, these findings indicate that regulating Akt/eNOS axis might be a potential strategy for DWH.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a critical regulator of cellular energy homeostasis and plays an essential role in metabolic pathways, and targeting AMPK signal might contribute to restored angiogenesis in diabetic wound [87]. Adenine accelerates wound healing in diabetic mice through improving re-epithelialization, reducing inflammation, and facilitating the angiogenesis via activating phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), increasing VEGF and Ang-1, and decreasing Ang-2. Additionally, Adenine ameliorates glucose and lipid metabolism by decreasing the levels of PPAR-δ and receptor for advanced glycation endproducts (AGE). Notably, Adenine elevates the expressions of p-AMPK, phosphorylated-glycogen synthase kinase 3β (p-GSK3β), and phosphorylated-acetyl-CoA carboxylase (p-ACC) in Hs68 cells [88], which indicates that targeting the AMPK/GSK3β/ACC axis may be the mechanism of Adenine for DWH.

2.3.2. Natural products target energy metabolism

BSP reverses HG-induced BMDM and cardiac microvascular endothelial cells (CMECs) viability reduction and suppresses intracellular ROS accumulation. BSP might act as an inhibitor of inflammasome activation, which rescues the increase of leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3), pro-IL-1β, and pro-caspase-1 in diabetic mice and HG-induced cells, blocks the cleavage of IL-1β and caspase-1, and up-regulates p-Akt and p-GSK-3β expression. Remarkably, BSP application obviously accelerates the wound closure rate in diabetic mice through promoting angiogenesis and blood capillary regeneration as well as upregulating the expression of CD31 [34]. Flavonoids such as RES and genistein exhibit pro-healing effect on diabetic wound through targeting sirtuins-mediated energy metabolic signaling pathway. RES facilitates DWH in mice and alleviates dysfunction of HG-treated HUVECs via restoring capillary density at wound site, increasing adenosine triphosphate (ATP) production, and decreasing cleaved-caspase-3, B-cell lymphoma-2 (Bcl-2) associated x protein (Bax)/Bcl-2, and ROS Furthermore, RES protects ECs against hyperglycemia by upregulating silent information regulator 1 (STRT1) and downregulating its downstream factor forkhead box O1 (FOXO1), thereby increasing the expression of c-Myc [35]. Hesperetin (HST) is a flavonoid isolated from citrus fruits and one of the vitamin P that ameliorates delayed wound healing and reduces wound diameter in diabetic rats, and promotes angiogenesis by inhibiting iron death, accompanied by the up-regulation of glutathione peroxidase 4 (GPX4) and sirtuin3 (SIRT3) and the down-regulation of acyl-CoA synthetase long chain family member 4 (ACSL4) [36]. In addition, lonicerin (LCR), a major glycoside from the edible plants of the Lonicera japonica species, reverses apoptosis and decrease of migration induced by t-butyl hydroperoxide (TBHP) in HUVECs and promotes tube formation of ECs. Meanwhile, LCR treatment also facilitates autophagy in HUVECs through upregulating Beclin-1, SIRT1, autophagy related 5 (ATG5), and microtubule-associated protein 1 light chain 3B (LC3B-II/LC3B-I), downregulating P62. LCR accelerates DWH in rats by elevating autophagy, new vessels formation, and COL deposition. However, SIRT1-siRNA inhibits autophagy, anti-apoptosis, pro-angiogenesis effects of LCR in TBHP-induced HUVECs, and SIRT1 knockdown attenuates wound healing effect of LCR in vivo [37]. Take together, targeting the SIRT1-autophagy axis might be a pivotal mechanism of LCR to enhance blood vessel regeneration during diabetic wound repair.

Moreover, mediating AMPK pathway to regulate energy metabolism is a critical mechanism of natural bioactives in improving wound angiogenesis under diabetic condition. Lentinan, a class of polysaccharides derived from shiitake mushrooms, promotes DWH through facilitating neovascularization and reducing inflammatory cell infiltration at wound site. Mechanistically, lentinan can promote the activation of AMPK and the increase of DAF16 expression in HG-induced HUVECs, thus promoting neovascularization [38]. The chemical structures of natural products targeting energy metabolism in diabetic wound angiogenesis are portrayed in Fig. 2.

2.4. ECM remodeling

2.4.1. Molecular signals

ECM provides structural support and signaling cues to guide ECs during blood vessel formation. In the context of DM, the dysregulation of TGF-β/Smad signaling contributes to impaired angiogenesis, delayed wound closure, and chronic inflammation [89]. ECM remodeling by MMPs is essential for creating an environment conducive to angiogenesis. MMPs are crucial regulators of the TGF-β/Smad pathway, affecting angiogenesis, and growth factor activation [12]. Thus, therapeutic strategies aimed at balancing MMP activity while enhancing TGF-β/Smad signaling hold promise for improving wound healing in diabetic patients.

GDF-10, a member of the TGF-β superfamily, accelerates wound closure in diabetic rats through by the new vessels, fibroblasts, and COL deposition and decreasing the proliferation of inflammatory cells via upregulating Smad3, VEGF, Ang-1, TGF-1β, and COL I/III and reducing MMP-9 [90]. In chronic wound tissues from diabetic patients, high MMP-9 levels are observed and the target genes of TGF-β including CTGF, COL1A1, and IL-6 are down-regulated. In addition, the expression of TGF-β pseudo-receptor bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is increased that contributes to inhibition of Smad2/3-dependent TGF-β signaling and impaired angiogenesis. Interestingly, tissue expression of BAMBI is dramatically up-regulated not only in chronic wounds, but also in acute wounds that transformed to chronic [91], suggesting that regulating BAMBI-mediated canonical TGF-β signaling might orchestrate revascularization in diabetic wound. Moreover, histone deacetylase 3 (HDAC3) and IL-1β are increased in diabetic mice and in HG + lipopolysaccharide (LPS)-treated macrophages, whereas HDAC3 inhibition promotes wound healing diabetic mice through facilitating angiogenesis and COL deposition via upregulating TGF-β, VEGF, and IL-10 [92].

Increased NETs in diabetic subjects are connected with impaired wound healing, especially the markers of NETs (citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and snail family transcriptional repressor 1 (Snail-1)) are increased in bloodstream of patients with DFUs. Besides, wound healing is delayed by the increase of NETs and the loss of PAD4 in STZ-induced mice and diabetic Padi4^−/− mice, whereas NETs inhibition and Smad2 knockdown ameliorate impaired wound healing by restoring angiogenesis and suppressing endothelial-to-mesenchymal transition (EndMT). NETs also suppresses tube formation of HUVECs by increasing EndMT markers and up-regulates p21 activated kinase 2 (PAK2) and Smad2, stimulates the colocalization of PAK2 and Merlin/NF2 and Smad2 and yes-associated protein (YAP), and induces the phosphorylation of Merlin/NF2 and the dephosphorylation of YAP in HUVECs [93]. Excessive MMP activity can lead to the release of anti-angiogenic factors from the ECM, counteracting the pro-angiogenic effects of TGF-β. Furthermore, the inhibitor of dipeptidyl peptidase-4 (MK0626) accelerates diabetic wound angiogenesis in mice via increasing SDF-1 and decreasing TGF-β3, TGF-β1, monocyte chemoattractant protein-1 (MCP-1), and MMP-9. Besides, MK0626 augments the number of bone marrow-derived mesenchymal progenitor cells and improves their migration [94].

In diabetic wounds, hyperglycemia, oxidative stress, and chronic inflammation disrupt wingless-type MMTV integration site family (Wnt)/β-catenin signaling, contributing to delayed healing and insufficient angiogenesis. IL-25 facilitates wound healing in diabetic mice by improving the COL deposition, re-epithelization, and angiogenesis via upregulating the expression of IL-17RB and β-catenin. Besides, IL-25 overexpression promotes tube formation of HUVECs treated by HG via upregulating VEGF, IL-17RB, and β-catenin [95], indicating that targeting Wnt/β-catenin signaling pathway may be a mechanism of IL-25 for DWH. Interestingly, the Wnt family member Wnt7a accelerates wound healing in diabetic rats through improving the re-epithelization and inhibit inflammation. Besides, Wnt7a treatment improves tube formation of HG or PA-induced ECs and reduces the number of apoptosis cells via increasing the expression of ICAM-1 and decreasing the levels of IL-6 and IL-8 [96]. Altogether, targeting the Wnt7a-mediated angiogenic axis might serve as promising strategy for DWH. Over-expression of CXXC-type zinc finger protein 5 (CXXC5) delays wound healing in diabetic mice and decreases the expression of β-catenin and proangiogenic factors, while the inhibitor of CXXC5 recovers the level of β-catenin and the downstream genes, thereby facilitates wound closure. In addition, impaired angiogenesis and ischemic limb loss or necrosis could be observed in acute hindlimb ischemia mouse model, whereas CXXC5 inhibition ameliorates the suppressed angiogenesis via increasing CD31, VEGF-A, and β-catenin [97].

2.4.2. Natural products target ECM remodeling

Flavonoids separated from various vegetables, fruits, and medicinal plants exhibit outstanding pro-healing property on diabetic wound, which improve ECM remodeling by increasing COL content. Kaempferol accelerates wound closure and epithelization, promotes thicker granulation tissue formation, increases COL content, and restores wound resistance in diabetic rats, with the increase of hydroxyproline [39]. Similarly, luteolin could improve wound healing in diabetic rats through promoting neovascularization, inhibiting inflammatory responses, and increasing hydroxyproline content [40]. A lot of flavonoids improve ECM remodeling to support angiogenesis in diabetic wound through targeting TGF-β-centered signaling pathways. Vicenin-2 (VCN-2), a flavonoid from edible herb Artemisia capillaris, can inhibit angiotensin-converting enzyme and regulate neovascularization, which accelerates wound healing, promotes granulation tissue formation and facilitates fibroblast proliferation and neovascularization in diabetic rats by upregulating VEGF and TGF-1β in wound tissue [30]. Quercetin is a flavonoid derived from multiple vegetables and fruits that accelerates wound healing in diabetic rats by promoting the growth of fibrous connective tissue and neovascularization and enhancing the thickness of skin via upregulating TGF-β1, IL-10, as well as VEGF and reducing MMP-9. Besides, local application of quercetin elevates the proliferation of fibroblasts, accelerates re-epithelialization, and facilitates neuronal regeneration [41,42]. HSYA intervention significantly promotes migration of human epithelial keratinocytes (HEKs) and tube formation of HUVECs, while reduces NO production in LPS-induced RAW264.7 cells. In addition, HSYA obviously accelerates the wound closure rate in diabetic rats through promoting thicker granulation tissue formation, re-epithelialization, vascular regeneration, COL growth, and the up-regulation of VEGF and TGF-β1 [43]. Besides, baicalin, a valuable flavone isolated from the root of Scutellaria baicalensis Georgi, improve wound angiogenesis in diabetic rats via regulating TGF-β/Smad signals. Baicalin accelerates wound closure and epithelization in diabetic rats and enhances thick granulation tissue via increasing Ang-1, Vegf-c, Tgfb, Tie-2, and Smad2/3 [44]. Likewise, HSP is a critical flavonoid from Citrus aurantium L., C. sinensis, which significantly accelerates wound healing and epithelialization in diabetic rats by activating TGF-β/Smad pathway [45].

Saponins like notoginsenoside R1 (NR1) and ginsenoside Rg1 (Rg1) improve angiogenesis in diabetic wound through improving ECM synthesis and remodeling as well. NR1 accelerates wound closure rate in diabetic rats through increasing epithelial tissue, promoting re-epithelialization and blood capillary regeneration, increasing CD31 levels, and downregulating caspase-3 expression. Additionally, NR1 intervention suppresses inflammatory response and promotes ECM remodeling during wound healing, with the decrease of MMP-3/9 and the increase of TGF-β and tissue inhibitor of metalloproteinases-1 (TIMP-1) [46]. Moreover, Rg1 also facilitates ECM remodeling through targeting TGF-β signal, which accelerates wound healing in diabetic mice, reduces the number of inflammatory cells, promotes thicker granulation tissue formation, and increases VEGF and TGF-β1 [47]. Moreover, allicin is a naturally occurring organosulfur compound separated from garlic that significantly promotes wound healing in diabetic rats through accelerating neovascularization, increasing COL deposition, and promoting the formation of fibroblast and monocyte [98]. Notably, natural product-based delivery systems have demonstrated superior therapeutic efficacy in ECM remodeling during DWH by improving compound stability, bioavailability, and targeted modulation of wound microenvironment. For instance, curcumin loaded chitosan nanoparticles embedded within COL-alginate scaffolds enhance the stability and solubility of curcumin and display promising pro-angiogenic effects in diabetic wounds by modulating ECM remodeling [99]. Additionally, curcumin/ZnO-loaded biodegradable nanofibrous scaffolds provide sustained curcumin release, and mimic the ECM structure to promote cell migration and proliferation, and effectively suppress inflammation and bacterial infection, thereby accelerating DWH [100]. The chemical structures of natural products targeting ECM remodeling in diabetic wound angiogenesis are shown in Fig. 4. The molecular mechanisms of ECM remodeling in diabetic wound angiogenesis and therapeutic effects of natural products are portrayed in Fig. 5.

Fig. 4.

Chemical structures of natural products targeting extracellular matrix (ECM) remodeling, oxidative stress, and non-coding RNAs (ncRNAs) in diabetic wound angiogenesis.

Fig. 5.

Molecular mechanisms of extracellular matrix (ECM) remodeling in diabetic wound angiogenesis and therapeutic effects of natural products. During diabetic wound healing (DWH), ECM remodeling plays a crucial role in regulating angiogenesis by controlling ECM degradation, synthesis, and reorganization, which requires the joint participation of fibroblasts, keratinocytes, endothelial cells (ECs) and immune cells, and the major signals involved in this process include wingless-type MMTV integration site family (Wnt)/β-catenin, transforming growth factor (TGF)-β, extracellular signal-regulated kinase (ERK)1/2, protein kinase B (Akt), and matrix metalloproteinases (MMPs). Abnormal ECM composition disrupts ECM integrity and function that impair EC-ECM interactions and angiogenic signaling, ultimately leading to defective neovascularization and delayed wound healing. Natural products contribute to ECM remodeling mainly via promoting TGF-β signal and activating fibroblasts, resulting in improved angiogenesis in diabetic wounds. EPCs: epithelial progenitor cells; HG: high glucose; PEDF: pigment epithelium-derived factor; BAMBI: bone morphogenetic protein and activin membrane-bound inhibitor; SDF-1: stromal cell-derived factor 1; VEGF: vascular endothelial growth factor; Wnt: wingless-type MMTV integration site family; GDF-10: growth differentiation factor 10; HIF-1α: hypoxia-inducible factor-1α; LPR6: low-density lipoprotein receptor protein; CXXC5: CXXC-type zinc finger protein 5; VCN-2: vicenin-2; HSYA: hydroxysafflor yellow A; Rg1: ginsenoside Rg1; HSP: hesperidin; NR1: notoginsenoside R1; Mϕ: macrophage; TNF-α: tumor necrosis factor α; IL: interleukin; ICAM-1: intercellular cell adhesion molecule-1; SP: substance P; eNOS: endothelial nitric oxide synthase; EndMT: endothelial-to-mesenchymal transition; Ang-1: Angiopoietin-1; YAP: Yes-associated protein; LAST: large tumor suppressor homolog; MST1: serine/threonine kinases Stk4; SCF: stem cell factor; ERK: extracellular signal-regulated kinase; PAK2: p21 activated kinase 2; TLR: Toll like receptor; NETs: neutrophil extracellular traps.

2.5. Oxidative stress

2.5.1. Molecular signals

In diabetic condition, hyperglycemia usually induces mitochondrial dysfunction, which enhances ROS production and reduces levels of SOD, catalase (CAT), and GPx [101], resulting in chronic oxidative stress that damages ECs, inhibit VEGF signaling, impairs fibroblast function, and inhibits keratinocyte proliferation-essential for wound closure [7]. Conversely, poor angiogenesis exacerbates oxidative stress by reducing oxygen and nutrient delivery to the wound site. Nrf-2/HO-1 signaling pathway is emerging as a crucial defense mechanism against oxidative stress and a key regulator of angiogenesis. Nrf-2 is a transcription factor that controls antioxidant response elements (AREs), regulating genes involved in redox homeostasis and cyto-protection. Under diabetic condition, Nrf-2 dissociates from kelch like ech associated protein 1 (Keap1) and translocate to the nucleus, where it binds to AREs in the promoter regions of genes [102]. SIRT1 ameliorates DWH by improving angiogenesis and inhibiting oxidative stress via activating Nrf-2/ARE pathway. Downregulation of SIRT1 in diabetic individuals is connected with delayed wound healing, while SRIT1 activator rescues wound healing through improving the function of ECs under HG condition via decreasing the levels of ROS, Nrf-2, and NAD(P)H dehydrogenase quinone 1 (NQO1) [82]. Interestingly, HDAC3 is a possible therapeutic agent for DWH by targeting the oxidative stress and improving angiogenesis, whose inhibition mitigates oxidative stress in HG + LPS-treated macrophages through decreasing ROS, NO, and malondialdehyde (MDA) and increasing SOD and glutathione (GSH). Meanwhile, HDAC3 inhibitor promotes DWH in mice through inhibiting the neutrophils and macrophages infiltration, alleviating oxidative stress, and facilitating the angiogenesis [92]. Thus, targeting Nrf-2/HO-1 signaling pathway-mediated oxidative stress may contribute to improved angiogenesis in diabetic wound.

2.5.2. Natural products target oxidative stress

A number of edible natural bioactives could promote angiogenesis at diabetic wound through modulating Nrf-2-mediated oxidative stress. Neferine, a dibenzylisoquino-line alkaloid separated from lotus seed, promotes wound closure in diabetic rats by upregulating Nrf-2, downregulating Keap1 and MDA, and rescuing the decreased activities of SOD, CAT, GPx, and glutathione S-transferase (GST). Meanwhile, neferine improves the formation of thicker granulation tissue and neovascularization, accelerates epithelialization, promotes COL synthesis, deposition and orientation, and down-regulates CD68 and CD163 levels [32]. In addition, PF, separated from the roots of Paeonia lactiflora Pall, promotes DWH in rats and HaCaT cells under HG condition through activating Nrf-2 and alleviating oxidative stress and apoptosis, with the increase of Ki67, SOD, GSH, and HO-1, and down-regulation of MDA and ROS [48]. Procyanidin B2 (PCB2) is a flavonoid derivative widely found in fruits and plants with anti-inflammatory, anti-tumor, and cardiovascular protective effects [103]. PCB2 exhibits promising therapeutic effect on DFU, which alleviates HG-induced EPC apoptosis and oxidative stress through activating Nrf-2, increases the tube formation of EPCs, reduces ROS, down-regulates 3-nitrotyrosine (3-NT) and 4-hydroxynonenal (4-HNE), and up-regulates NQO-1 and catalase. In addition, PCB2 promotes wound healing in diabetic mice via improving the antioxidant status of wounds, accelerating wound re-epithelialization, increasing capillary density, promoting neovascularization, and reducing MDA and CD34/VEGFR2 [49].

Additionally, multiple natural compounds facilitate angiogenesis during DWH through balancing the oxidative and antioxidant enzymes at the trauma site. Kirenol is a naturally occurring diterpenoid with promising wound healing effect, which reduces wound diameter, promotes re-epithelialization and total COL content of wound tissues, accelerates neovascularization, and mitigates oxidative stress through upregulating the levels of SOD, CAT, GPx, and GST [29]. Dehydrogingerone (DHZ) derived from the rhizomes of Zingiber officinale (Ginger) has a wide range of pharmacological effects, especially improving angiogenesis. DHZ mitigates oxidative stress and lipid disorders in diabetic rats by upregulating the content of high-density lipoprotein (HDL) and GSH and down-regulation that of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and MDA. In addition, DHZ accelerates wound contraction, facilitates granulation tissue formation and re-epithelialization, enhances COL deposition, and facilitates ECM and angiogenesis in diabetic rats [50]. In addition, alginate (SARP), a class of naturally derived polysaccharides, improves migration and tube formation of HUVECs under diabetic condition through upregulating the expression of VEGF and improves wound healing in diabetic rats through increasing the expression of CD31, decreasing MDA and glutathione oxidized (GSSG), and increasing GSH and SOD [51].

Several natural bioactives alleviate oxidative stress in diabetic wound through reducing ROS production and thereby promote angiogenesis. Anemoside B4 is a saponin derived from Pulsatilla chinensis (Bunge) Regel, which facilitates the M2 polarization through attenuating the inflammatory response and inhibiting the production of ROS. Meanwhile, it improves wound healing in diabetic mice through promoting the production of granulation tissue and neovascularization via increasing CD31 [52]. Likewise, PTE improves angiogenesis through alleviating oxidative stress in HG-induced HUVECs and diabetic rats and inhibiting the production of ROS, methylglyoxal, 8-oxo-dGformation, as well as 3-NT [19]. Interestingly, smart delivery systems could improve the ROS-targeting ability of natural products in diabetic wounds. Quercetin-loaded supramolecular hydrogel controls drug release by dual responsiveness to ROS and glucose in diabetic wounds, which inhibits oxidative stress and bacterial infection and promotes angiogenesis [104]. Likewise, ROS responsive hydrogel-engineered EPCs-targeted exosomes composite AS-IV delivery system (PF-PEG@ASIV-EXO) can deliver AS-IV under high ROS levels, which ameliorates ferroptosis and promote angiogenesis to accelerate DWH [105]. The chemical structures of natural products targeting oxidative stress in diabetic wound angiogenesis are shown in Fig. 4.

2.6. ncRNAs

2.6.1. Molecular signals

MicroRNAs (miRNAs) play multifaceted roles in angiogenesis during DWH by regulating key processes such as ECs function, response to hypoxia, inflammation, and ECM remodeling. miR-200b and miR-15b are classical anti-angiogenic miRNAs that serve for delayed wound healing in DM. Up-regulation of miR-200b in HG-irritated HUVECs causes decreased tube formation, with increase of IL-1β and down-regulation of VEGF, Jagged1, Notch1, and Hes1. Notably, these inhibitory effects of miR-200b are reversed by Notch pathway inhibitor [106]. Moreover, anti-miR15b and anti-miR200b accelerate wound healing in db/db mice through improving epithelialization, COL deposition, and angiogenesis, with up-regulation of VEGF, VEGFR-2, Ang-1, and TK endothelial (TEK) [107].

Hypoxia is one of the most critical stimuli for angiogenesis at the diabetic wound site, which could decrease the levels of miR-196a-5p and promote migration and proliferation of ECs. Increased miR-196a-5p in ECs targets and represses the translation of high mobility group A2 gene (HMGA2) that further inhibits the accumulation of HIF-1α, which thereby negatively regulates angiogenesis and delays wound healing in diabetic mice. Notably, HMGA2 knock-down exhibits similar effects as miR-196b-5p overexpression in ECs [108]. In addition, increased miR-217 in wound site of diabetic patients and rats inhibits HIF-1α and VEGF, leading to impaired wound closure. Nevertheless, miR-217 inhibitor accelerates DWH in rats by improving angiogenesis via increasing HIF-1α, VEGF, VEGFR2, eNOS, and MMP-2 [109]. In addition, miR-135a-3p is increased in db/db mice and skin tissue from diabetic patients that hinders wound angiogenesis through downregulating CD31, huntingtin interacting protein 1 (HIP1), and p38 and inhibiting tube formation of HUVECs. Notably, inhibition of HIP1 or p38 suppresses the functions of ECs despite miR-135a-3p overexpression [110], suggesting that inactivating miR-135a-3p/HIP1/p38K signaling axis might contribute to improved angiogenesis in diabetic wound.

miR-155 is another anti-angiogenic miRNA that impedes wound healing in diabetic rats by inhibiting granulation formation and aggravating inflammatory response. miR-20b-5p is significantly up-regulated in exosomes from diabetic patients that obviously inhibits wound healing in mice, while miR-20b-5p knock-out promotes angiogenesis in wound site of diabetic mice. In addition, miR-20b-5p could suppress angiogenic function of HUVECs via inhibiting Wnt9b/β-Catenin signaling pathway, while these effects are mimicked by Wnt9b knock-down [111]. Moreover, up-regulated miR-195-5p and miR-205-5p is observed in extracellular vesicles (EVs) derived from wound fluids of DFU patients, which represses tube formation of HUVECs by decreasing VEGF-A [112].

Importantly, targeting pro-angiogenic miRNAs like miR-21 and miR-221-3p that are down-regulated in diabetic wound is a possible therapeutic strategy for diabetic wound. Keratinocyte-derived micro-vesicles (MVs) miR-21 accelerates wound angiogenesis in diabetic rats via increasing VEGF. Besides, MV miR-21 treatment promotes migration and differentiation of fibroblasts by upregulating α-SMA and N-cadherin that thereby facilitates the tube formation of co-cultured HUVECs, whereas these effects are abrogated by miR-21 inhibitor. Moreover, miR-21 increases IL-6, IL-8, MMP-1, MMP-3, and p-ERK1/2 and decreased TIMP-3, TIMP-4, phosphatase and tensin homolog (PTEN), and reversion inducing cysteine rich protein with kazal motifs (RECK), which contributes to finely-tuned inflammation and ECM remodeling [113]. Moreover, miR-221-3p from EPCs-derived exosomes improves wound healing in diabetic mice by targeting and decreasing homeodomain-interacting protein kinase 2 (HIPK2). Additionally, both miR-221-3p mimic and HIPK2 knock-down improves tube formation of HUVECs induced by HG [114], suggesting that miR-221-3p/HIPK2 is a promising therapeutic target for impaired angiogenesis in diabetic wound.

Long ncRNAs (lncRNAs) contribute to angiogenesis in diabetic wound mainly through regulating the expression of VEGF, influencing the function of ECs, and interfering with hypoxia-induced pathway. lncRNA SNHG8 and transient receptor potential melastatin 7 (TRPM7) are upregulated in HG-treated ECs, which decrease the expression of p-eNOS, NO, and ERK1/2, leading to impaired tube formation. Intriguingly, SNHG8 knock-down reverses the dysfunction of HUVECs caused by HG. In addition, TRPM7 knock-down exerts similar effects on ECs by increasing the expression of ERK1/2 [115]. lncRNA ANRIL and GAS5 ameliorate diabetic wound via targeting HIF-1α/VEGF-A signaling pathway. lncRNA ANRIL and GAS5 are decreased in skin tissues from DFU patients, diabetic mice, and HG treated ECs, whose overexpression facilitates wound angiogenesis in diabetic mice by upregulating VEGF-A and HIF-1α, while silence of HIF-1α reverses these effects of ANRIL and GAS5 [116,117]. Moreover, lncRNA H19 promotes HIF-1α histone H3K4me3 methylation and upregulates HIF-1α through recruiting enhancer of zeste homolog 2 (EZH2), which thereby accelerates fibroblast activation and facilitates wound healing in diabetic mice, as reflected by the up-regulation of alpha 1 chain of type I collagen (Col1A1), α-SMA, and VEGF [118]. The roles of ncRNAs in regulating angiogenesis during DWH are shown in Fig. 6 and Table S2 ([[106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118]]).

Fig. 6.

Roles of non-coding RNAs (ncRNAs) in regulating angiogenesis during diabetic wound healing (DWH). ncRNAs especially microRNAs (miRNAs) and long no-coding RNAs (lncRNAs) contribute to angiogenesis in diabetic wounds through regulating the function of endothelial cells (ECs) and keratinocytes, modulating the polarization of macrophages, and mediating the cellular communications via targeting signals especially hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF), extracellular signal-regulated kinase (ERK), transforming growth factor (TGF)-β, Notch1, Wnt family member 9B (Wnt9b)/β-catenin, and huntingtin interacting protein 1 (HIP1)/p38. FUS: fused in sarcoma; EZH2: enhancer of zeste homolog 2; DM: diabetes mellitus; IGF: insulin-like growth factor; Mϕ: macrophage; TAF15: TATA-box binding protein associated factor 15; EPC: epithelial progenitor cell; ECM: extracellular matrix; miRNAs: microRNAs; SDF-1α: stromal cell-derived factor 1α; α-SMA: α-smooth muscle actin; IL: interleukin; MMPs: matrix metalloproteinases; TIMP: tissue inhibitor of metalloproteinases; BMACs: bone marrow-derived angiogenic cells; HIPK2: homeodomain interacting protein kinase 2; TNF-α: tumor necrosis factor α; HG: high glucose; TGF-β: transforming growth factor-β; COL: collagen; NO: nitric oxide; IRE1α: inositol-requiring enzyme 1α; ANGPT1: angiopoietin 1; VEGFR: vascular endothelial growth factor receptor-1; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal-regulated kinase; Bcl-2: B-cell lymphoma-2; HMGA2: high mobility group A2 gene; TRPM7: transient receptor potential melastatin 7; MSCs: mesenchymal stem cells; Wnt9b: wnt family member 9b.

2.6.2. Natural products target ncRNAs

Rg-1 (Fig. 4) intervention accelerates wound healing in diabetic rats and promotes proliferation, migration, as well as tube formation of HG-induced HUVECs. In addition, Rg-1 reverses the up-regulation of miR-23a in HUVECs, resulting in the elevation of target gene IRF-1 and the increase of Nox, iNOS, as well as VEGF [53], indicating that Rg1 facilitates angiogenesis in DWH process by elevating iNOS via targeting miR-23a/IRF-1 axis. In addition, Rg1 also reverses apoptosis and intracellular oxidative stress in HG-treated ECs via inhibiting cleaved-caspase 3/9, MDA, Bax, and miR-489-3p, upregulating SOD, NO, and Bcl-2, and promoting the phosphorylation of phosphoinositide 3-kinase (PI3K), Akt, and eNOS. HG or STZ-induced down-regulation of miR-489-3p suppresses SIRT1 expression, thereby decreasing VEGF levels, which consequently inhibits the expression of CD31 and eNOS, ultimately delaying wound neovascularization. However, Rg1 can reverse the decrease of miR-489-3p, promote angiogenesis, and accelerate wound healing [54], suggesting that Rg1 promotes angiogenesis and alleviates DM-induced ulcers via regulation of the miR-489-3p/SIRT1 axis. β-sitosterol (Fig. 4) is a phytosterol derived from lipid-rich plant foods that facilitates wound healing in diabetic rats through improving the angiogenesis, epithelization, and COL formation. β-sitosterol application suppresses inflammation by increasing the number of M2 macrophages, down-regulates the levels of rno-miR-144-3p and rno-miR-677-5p, and up-regulates the levels of rno-miR-138-5p, and rno-miR-490-5p in diabetic rats [55].

3. Chemical structure-guided angiogenesis activity

The structure-activity relationship (SAR) of natural products determine how they interact with molecular targets, influencing their efficacy in angiogenesis, oxidative stress reduction, and inflammation control during DWH. Flavonoids share a common backbone structure, consisting of two aromatic rings (A and B) connected by a heterocyclic C-ring (Fig. 7A(I)). The hydroxyl groups, double bonds, and glycosylation patterns affect their anti-inflammatory and anti-oxidative abilities in ECs, which thereby dictate their pro-angiogenic effect. For flavonoids, the presence of 5,7-dihydroxyl groups on the A-ring and a 2,3-double bond along with a 4-keto group on the C-ring are key features for suppressing adhesion molecule expression. Meanwhile, hydroxyl groups on the B- and C-rings contribute to antioxidant properties (Fig. 7A(II)). These findings suggest that only hydroxyl flavones and flavonols effectively reduce endothelial adhesion molecule levels in TNF-α-treated HAECs [119]. Intriguingly, the ability of flavonoids to enhance eNOS expression in H₂O₂-treated ECs is largely determined by specific structural features, including the absence of 3-O- and 7-O-glycosylation (C- and A-rings, respectively), 3-hydroxylation of the C-ring, and 4′-O-methoxylation; the presence of a C2=C3 double bond and a ketone at C4 (C-ring); and 3′-hydroxylation of the B-ring [120] (Fig. 7A(III)).

Fig. 7.

Structure-activity relationship (SAR) of natural products on angiogenesis in diabetic wound. The chemical structure of natural products critically determines their ability to modulate endothelial inflammation, oxidative stress, and angiogenesis. Variations in hydroxylation, glycosylation, methoxylation, steric hindrance, and stereoisomerism affect key signaling pathways (e.g., endothelial nitric oxide synthase (eNOS), protein kinase B (Akt)/extracellular signal-regulated kinase (ERK), heme oxygenase-1 (HO-1), peroxisome proliferative activated receptor gamma (PPARγ), thereby influencing endothelial cell (EC) survival, migration, and tube formation, highlighting the importance of SAR-guided optimization of natural compounds for enhancing pro-angiogenic effects in diabetic wound healing (DWH). (A) The SAR of flavonoids: the parent structure of flavonoids (i), the relationship between the substitution of hydroxyl groups and double bonds and oxidative stress and adhesion molecule (ii), the regulation of eNOS by hydroxylation and glycosylation at different positions (iii), the regulation of reactive oxygen species (ROS) inhibitory effect by different substituents (iv), the relationship between B-ring substitution and the expression of HO-1 (v), the SAR of glabridin on oxidation (vi), the relationship between the number of hydroxyl groups in B-ring and antioxidant capacity (vii). (B) The SAR of salidroside on angiogenesis. (C) The relationship between stereoisomerism and physiological effects. (D) The different substitution patterns of phenolic acid components on the proliferation of ECs. ROS: reactive oxygen species; LDL: low-density lipoprotein.

In addition, the anti-oxidative stress effect of flavonoids on vascular ECs is also affected by the type and number of sugar substituents. Specifically, cyanidin and the rutinose substitution of 3-O-glycosylation (cyanidin-3-O-rutinoside) cannot inhibit ROS production in 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH)-treated ECs, while 3-O-glycosylation and 3-5-di-glycosylation enhance the ability of aglycone to scavenge ROS, of which, cyanidin-3-5-diglucoside exhibits the strongest inhibitory effect against intracellular ROS [121] (Fig. 7A(IV)). Besides, the protective effect of flavonoids such as anthocyanins on ECs is structure-dependent. Non-acylated forms exhibit stronger inhibition of TNF-α-induced vascular cell adhesion molecule 1 (VCAM-1) and ICAM-1 expression in HMEC-1 compared to their cinnamic acid-acylated counterparts, which is in accordance with their corresponding antioxidant activity [122]. Another study demonstrated that flavonoids containing ortho-dihydroxyl groups and an α, β-unsaturated catechol moiety are potent inducers of HO-1 expression in HAECs and are also highly prone to oxidation. Notably, only quinone derivatives of caffeic acid were shown to mitigate oxidant-induced endothelial dysfunction in mouse aortic rings through an HO-1 dependent mechanism [123] (Fig. 7A(V)), suggesting that the oxidized, rather than reduced, forms of flavonoids are responsible for HO-1 activation. In addition, the 2′ hydroxyl group on ring B and hydrophobic moiety of isoflavan are crucial for the antioxidant capacity of some flavonoids. For example, glabridin, hispaglabridn A, hispaglabridn B, and 4′-O-methylglabridin with similar chemical structure are found to suppress AAPH-induced LDL oxidation compared with other compounds separated from licorice root [124] (Fig. 7A(VI)). Notably, both kaempferol and quercetin display outstanding antioxidant effect on ECs, while quercetin displays stronger antioxidant activity and less toxicity than kaempferol, which might be connected with higher the numbers of -OH moieties on the B-ring [125] (Fig. 7A(VII)), demonstrating that the varying number of -OH groups on the B-ring of flavonols may influence both their antioxidant properties and potential toxicity, significantly impacting their biological activity such as angiogenesis and immune-EC adhesion.

In addition, the pro-angiogenic effect of salidroside is affected by the substituents and steric hindrances. Specifically, the methoxy-substitution and fluoro-substitution in the phenolic moiety part enhance the pro-angiogenic effect of salidroside, which increase the levels of HIF-1α, PDGF-BB, VEGF-A, and ANG1 in myoblasts, whereas the methoxy-substitution in the glycosyl ring inhibits the pro-angiogenic effect of salidroside. Besides, insertion of a methylene and a benzene ring between the glycosyl ring and the phenolic moiety part changes the steric hindrance, linker length, and skeleton rigidity of salidroside thus enhances the pro-angiogenic effect of salidroside [126] (Fig. 7B). Notably, the structural difference between stereoisomers may affect the physiological outcomes of natural compounds. 20(S)-Rg3 and 20(R)-Rg3 stereoisomers exhibit distinctive differential angiogenic activities in vitro and ex vivo, of which, 20(S)-Rg3 possesses more potent effect in promoting proliferation, migration and tube formation of ECs as well as endothelial sprouting than 20(S)-Rg3. Consistently, 20(S)-Rg3 treatment rather than 20(R)-Rg3 induces the activation of Akt/ERK-eNOS signal in HUVECs and 20(S)-Rg3 display 10-fold stronger promotion on PPARγ transcriptional activity than 20(R)-Rg3 [127] (Fig. 7C). The protective effect of phenolic acid components against H₂O₂-induced oxidative stress in ECs is associated with the nature of the substituents. For example, cinnamic acid derivatives bearing three methoxyl groups significantly promote EC proliferation, and those containing a single or no ligustrazine moiety exhibit greater activity than bis-ligustrazine-substituted counterparts. Moreover, introducing ligustrazine to the hydroxyl group of capsaicin results in superior activity compared to cinnamic acids alone [128] (Fig. 7D), highlighting the importance of its substitution position in mono-ligustrazine derivatives.

Taken together, these evidences indicate that modifying the chemical structure of edible natural flavonoids, polyphenols, saponins, and other compounds could improve their ability to protect ECs against inflammation, oxidative stress, and apoptosis, which may contribute to the development of novel small molecule drugs that target and enhance the functions of ECs under diabetic condition, thereby facilitating angiogenesis in diabetic wounds.

4. Challenges and future perspectives

Angiogenesis plays a pivotal role in wound healing, which is orchestrated by a dynamic network of signaling pathways that regulate EC proliferation, migration, and vascular stabilization. However, in diabetic condition, this process is disrupted by hyperglycemia, oxidative stress, and chronic inflammation, leading to delayed wound repair. Mechanistically, impaired wound angiogenesis in diabetic subjects is associated with aberrant activation/inhibition of multiple signaling pathways, which principally include ncRNAs-mediated angiogenic axis, HIF-1α/VEGF, NF-κB, Akt, TGF-β/Smad, Wnt/β-catenin, STAT, and etc. Current evidence suggests that the vast majority of signaling pathways are focused on regulating EC function, including promoting their proliferation, migration, and neovascularization capacity, and decreasing their inflammation, oxidative stress, and apoptosis. However, it is worth noting that intercellular cross-talk is also involved in angiogenesis in DWH, including factors secreted by macrophages, keratinocytes, and fibroblasts that can affect EC function, suggesting that targeting angiogenesis in DWH can also be achieved by modulating paracellular pathways, a strategy that may be more responsive to the diabetic wound complex microenvironment.

Natural products, with their diverse bioactivities, offer promising therapeutic avenues to target angiogenic dysfunction in diabetic wounds. Flavonoids, polyphenols, polysaccharides, glycosides, and alkaloids have shown potential in modulating critical signaling pathways. Among them, flavonoids and polyphenols with potent antioxidant and anti-inflammatory properties help restore HIF-1α/VEGF signaling, reduce NF-κB activity, and enhance EC proliferation and migration. In addition, a large proportion of polysaccharides and glycosides possess immunomodulatory effects that support macrophage polarization toward the M2 phenotype, boosting STAT6 and VEGF-driven angiogenesis. Besides, some alkaloids can target oxidative stress and mitochondrial dysfunction, promoting Akt and TGF-β signaling pathways critical for vascular repair. However, challenges such as bioavailability, stability, and delivery mechanisms limit their clinical application. Current studies tend to prepare these natural products into hydrogels, microneedles, or nanofibrous scaffold, which improve the stability and solubility of natural products. These formulations intelligently release natural products in response to the ROS and pH at the wound site and provide structural support for cell proliferation and migration, thereby enhancing the therapeutic effects to promote DWH. Notably, the topical cream (ON101), containing active pharmaceutical ingredients extracted from Plectranthus amboinicus and Centella asiatica, has been approved for marketing authorization in Chinese. Both preclinical studies and phase III clinical trials of ON101 have been demonstrated to restore the M1/M2 macrophage imbalance induced by hyperglycemia, thereby promoting the transition of the wound from the inflammatory phase to the proliferative phase with increase of COL synthesis and stem cell infiltration, consequently accelerating tissue repair and DFU wound healing. In addition, the ability of a number of different types of natural products to target and modulate the same signaling pathway to promote neovascularization suggests a need to study their SARs.

Recent advances in chemical proteomics offer a powerful tool to identify protein targets of natural products and clarify how their distinct chemical scaffolds confer pathway-specific biological effects. For instance, flavonoids like quercetin and kaempferol have been shown to interact with kinases or transcription factors involved in VEGF or PI3K/Akt signaling [129,130], while alkaloids like oxymatrine may bind to SCP2 to modulate fibrosis [131]. However, chemical proteomics studies specifically focused on the angiogenic processes in DWH remain limited. This highlights a significant gap in current research and underscores the need for future studies to integrate structural characterization with proteomics-based target identification strategies, such as activity-based protein pro filing or thermal proteome profiling [132,133], to systematically uncover how natural products exert their pro-angiogenic effects under diabetic conditions.

Notably, several key mechanistic and translational challenges remain unresolved so far. For instance, it is still unclear how specific ECM components such as fibronectin, COL, proteoglycan, dynamically interact with ECs and immune cells in a temporal and spatial manner under diabetic conditions. Furthermore, the relative contribution of MMP subtypes and TIMPs in orchestrating angiogenic versus fibrotic responses remains to be elucidated. Current in vitro models often fail to recapitulate the complex ECM architecture and mechanical properties of diabetic wounds, while in vivo models, such as the db/db mouse, do not fully mimic human wound chronicity and heterogeneity. In addition, challenges from a translational perspective include the lack of ECM-targeted therapeutic agents with validated angiogenic efficacy in clinical settings and the difficulty in delivering ECM-modulating natural products with spatial specificity and sustained activity. Future studies should prioritize the development of advanced 3D co-culture systems and biomimetic wound models to dissect ECM-cell interactions. Furthermore, it is essential to explore how natural products can be engineered via nanotechnology or scaffold incorporation to selectively regulate ECM degradation or synthesis in a wound stage-specific manner.

5. Conclusion

In conclusion, angiogenesis is a critical determinant of DWH, and its impairment necessitates targeted therapeutic approaches, among which, natural products-based therapeutic strategies display great potential in it through supporting angiogenesis. Despite the promising results of preclinical studies, several challenges hinder clinical translation, including limited large-scale clinical trial data, variability in compound purity and composition (especially polysaccharides), and lack of standardized outcome measures. Moreover, issues such as pharmacokinetics, optimal dosing, delivery systems, and potential off-target effects must be rigorously addressed in human studies. Thus, future research might focus on optimizing the delivery and bioavailability of natural products, exploring combination therapies, and integrating personalized medicine approaches to enhance therapeutic outcomes. This dual focus on mechanistic insights and translational solutions holds promise for transforming the management of diabetic wounds and improving the quality of life for affected patients.

CRediT authorship contribution statement

Junren Chen: Writing – original draft, Conceptualization. Siqi Qin: Writing – original draft. Ziwei Xing: Writing – original draft. Cheng Peng: Writing – review & editing, Supervision, Project administration, Funding acquisition. Dan Li: Writing – review & editing, Supervision, Project administration, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary data

The following are the Supplementary data to this article: