The mechanism of C1q/TNF-related proteins (CTRPs) in atherosclerosis associated with type 2 diabetes mellitus

Abstract

Increasing evidence suggests that C1q/tumor necrosis factor-related proteins (CTRPs), as the adipokine superfamily, are secreted by adipose tissues. They play an important role in diabetic cardiovascular pathology. Diabetic vascular complications pose a significant threat to human health and are the primary cause of disability and mortality in diabetes. Adipose tissue dysfunction, including secretion and dysfunction of adipokines, is closely associated with diabetic vasculopathy. However, the expression levels of CTRPs show heterogeneity in different pathophysiological states, and their potential mechanisms of action have not been elucidated. Therefore, this review aims to summarize and discuss the differences in circulating expression of CTRPs in diabetic patients, as well as their roles and mechanisms in diabetic vasculopathy, to offer new insights and targets for the prevention and treatment of diabetic vasculopathy.

Supplementary Information

The online version contains supplementary material available at 10.1186/s40001-025-03188-w.

Introduction

Vascular complications are the leading cause of disability and death in individuals with diabetes, posing a significant global public health challenge [1]. Diabetic vasculopathy encompasses both macro-vasculopathy [2] and micro-vasculopathy [3, 4]. In 2021, adults aged 20–79 who died from diabetes or its complications accounted for 12.2% of all deaths [5]. Vascular complications associated with diabetes is a complex and progressive disease. Their mechanisms involve endothelial dysfunction, proliferation and migration of vascular smooth muscle cells (VSMCs), which is associated with the dysregulation of oxidative stress, inflammation, autophagy, senescence and apoptosis [6].

A relatively new discovery, the C1qTumor necrosis factor-related proteins (CTRPs) [7], form a superfamily of adipokines, currently consisting of 15 members (CTRP1-15) [8]. Although the CTRP family is widely expressed in various organs and tissues, it is mainly a type of chemical hormone secreted by adipose tissue and exerts corresponding biological functions. Most of the current research on the secretion sources of CTRPs in adipose tissue has focused on white adipose tissue mainly composed of epididymal fat pads. In addition, some studies have shown that the expression of CTRP1, CTRP2 and CTRP7 is rather limited to preadipocytes [9]. However, there is also a literature report that CTRP1 can be secreted and expressed in the epicardial adipose tissue of people capable of Browning, and is involved in the pathogenesis of congestive heart failure [10]. CTRP5 negatively regulates the browning of white adipose tissue by modulating autophagy [11]. It has also been reported that a considerable amount of CTRP12 is expressed in the white and brown adipose tissues of mice with a C57BL/6 genetic background [12]. Given the above general and diverse exploration results of fat sources, more research is needed in the future to refine the secretion of CTRPs in beige adipose tissue and brown adipose tissue.

CTRPs exhibit structural and functional similarities to adiponectin and play a pivotal role in modulating energy metabolism, immune responses, inflammatory processes, as well as a myriad of physiological and pathological mechanisms within the organism [13, 14]. CTRPs, just like adiponectin, can bind to two isotypes of adiponectin receptors, adiponectin receptor (AdipoR)1 and AdipoR2. In addition, mediate the phosphorylation of various substrates, including Akt, AMPK, MAPK, S1P/cAMP, TGF-β and ERK1/2. As an irreplaceable central molecule in the regulatory network, it participates in multiple major intracellular signaling pathways [15].

CTRPs are regulated by multiple stimulating factors under physiological and pathological conditions. First, under physiological conditions, the body's energy metabolism demands can stimulate the expression of certain members. For instance, CTRP9 can promote fat oxidation and energy metabolism by activating the AMPK signaling pathway under physiological conditions [16]. Second, nutrients in the diet, such as fatty acids, can regulate the expression of members of the CTRP family. For instance, saturated fatty acids can induce the expression of CTRP5 in adipocytes [17]. Third, exercise can increase energy expenditure and metabolic demand, thereby stimulating the expression of CTRP9, which in turn promotes vasodilation by activating the AMPK signaling pathway [18]. On the other hand, stress states such as inflammation, oxidative stress, tissue damage or ischemia–reperfusion, as well as metabolic disorders, such as hyperglycemia and hyperlipidemia, can all affect the secretion level of CTRPs. Numerous studies have demonstrated that these secreted proteins are essential in preserving vascular homeostasis, particularly in the context of diabetes and its related vascular complications [19–21]. Therefore, this review focuses on the roles and mechanisms of different CTRPs members in the development of diabetic vascular complications (Fig. 1).

Fig. 1.

Summary of the mechanism of CTRPs in DAA

Circulating levels of CTRPs in patients with diabetic vasculopathy

CTRPs in macrovascular complications of T2DM

Atherosclerosis is the primary pathological change in diabetic macro-vasculopathy. Atherosclerosis is characterized by the lesion of the affected artery starting from the intima, followed by lipid accumulation, fibrous tissue hyperplasia and calcium deposition successively, and the gradual degeneration and calcification of the arterial middle layer. On this basis, intraplaque hemorrhage, plaque rupture and local thrombosis occur secondary. Because the lipids accumulated in the intima of the artery appear yellow and atherosclerotic, it is called atherosclerosis [22]. The formation of atherosclerosis in patients with type 2 diabetes may be related to the mutual influence and reinforcement of multiple factors, such as hyperglycemia, hyperlipidemia, obesity, insulin resistance, chronic inflammation, and endothelial injury. Compared with normal blood sugar, hyperglycemia leads to increased cell permeability, lipid deposition in the subcutaneous tissue, accelerating the early formation of fat streaks. Monocytes and macrophages enter the subcutaneous tissue to phagocytize lipids and become foam cells, participating in the formation of fat spots. Under the continuous influence of factors, such as lipid deposition and infiltration of various inflammatory cells, the fibrous cap becomes thinner, the stability of the plaque decreases, and the plaque develops cracks, erosion or rupture. They can accelerate the exudation in the areas prone to vascular lesions, thereby accelerating the formation of necrotic cores during atherosclerosis. The occurrence and development of cardiovascular and cerebrovascular events are ultimately accelerated [23]. However, its occurrence mechanism is not yet fully clear. It may also include low-density lipoprotein modification, the formation of advanced glycation end products, oxidative stress, and the regulation of microRNA levels by blood vessels, etc. [24]. Although CTRPs has been relatively poorly studied in diabetic atherosclerosis, circulating CTRP9 levels vary (e.g., reduced in [27] vs. elevated in [24]), potentially explaining 20–58.4% of expression differences across studies. In 2014, Jung and colleagues investigated whether serum CTRP9 concentration was associated with atherosclerosis by measuring brachial ankle pulse wave velocity (baPWV) in subjects with type 2 diabetes. The result showed that serum CTRP9 concentration was significantly And positively associated with arterial stiffness in patients with type 2 diabetes [25]. A study by Asada et al. in which a positive association between serum CTRP9 levels and atherosclerosis in T2DM patients was demonstrated [26].Two years later, Moradi et al. revealed that circulating CTRP9 levels were associated with an increased risk of T2DM and CAD. They found an independent association of CTRP9 levels with soluble adhesion molecules in patients with CAD and T2DM [27]. In recent years, there has been a growing number of studies on CTRP9 in T2DM, with increasingly in-depth exploration of its physiological and pathological mechanisms. Building on this foundation, our team conducted a meta-analysis, the findings of which revealed a notable decrease in circulating CTRP9 levels in T2DM patients with vascular complications [28]. It is necessary to continue to explore the role and mechanism of CTRP9 in diabetic vascular complications.

CTRP3 is a potent anti-inflammatory adipokine that inhibits pro-inflammatory pathways in monocytes and microcells during the development of CAD. However, there are few studies in type 2 diabetes mellitus And type 2 diabetes with vascular complications patients. For example, Fadaei et al. initially investigated the association between CTRP3 and markers of diabetic metabolism and inflammation [such as body mass index (BMI), insulin, HOMA-IR, glycosylated hemoglobin (HbA1c) and TNF-α] in 2016. The findings revealed that the level of serum CTRP3 was independently linked with BMI [29]. A study published in the journal Diabetes in 2020 found that T2DM patients with CAD [30], had decreased CTRP3 expression, suggesting that CTRP3 may be involved in the development of cardiovascular complications in T2DM. A recent meta-analysis indicated that diabetes patients with macrovascular complications had significantly lower levels of CTRP3 compared to healthy controls. Subgroup analyses revealed a significant impact of gender and BMI on this association [31]. Recent studies have demonstrated that the CTRP5 protein is widely expressed across various tissues, with notable prevalence in the stromal vascular cell fraction. This protein circulates abundantly in plasma and plays a regulatory role by inhibiting the secretion of key adipokines, such as resistin, leptin, and adiponectin [32]. CTRP5 is closely involved in regulation of cardiovascular metabolism and displays a counter-regulatory connection with CTRP3 [33]. Based upon above-mentioned evidence, our research team initially investigated the role of CTRP5 in T2DM. We discovered that serum CTRP5 levels were significantly elevated in T2DM patients compared to healthy controls, and were also markedly linked to carotid artery atherosclerosis (CAS). The CTRP5 levels were higher in T2DM patients with CAS compared to those without CAS [34]. The study by Majidi et al. demonstrated that CTRP5 and CTRP1 concentrations were independently associated with carotid intima–media thickness [35]. These adipokines may have a potential causal relationship with atherosclerosis in T2DM patients.

Muendlein et al. carried out a prospective clinical trial and discovered that higher levels of CTRP1 at the beginning of the study were significantly linked to obesity, metabolic syndrome, and T2DM. In addition, increased CTRP1 levels were significantly associated with negative cardiovascular outcomes [36]. In a 2020 clinical observational study was observed that serum CTRP1 levels were significantly higher in the CAD + T2DM group compared to the control group. This finding aligns with earlier results reported by Muendlein et al., further supporting the association between elevated CTRP1 levels and these metabolic conditions. In addition, the study also found that the serum CTRP7 was significantly reduced in the T2DM group and the CAD + T2DM group [37]. Beginning in 2022, studies have reported the relationship between CTRP4 and T2DM. However, conflicting research results have surfaced: the study by Liu et al. indicated that serum CTRP4 concentration in T2DM patients with coronary artery disease (CAS) was lower than in T2DM patients without CAS, and that serum CTRP4 level was inversely correlated with the risk of CAS in T2DM patients [38]. Other studies have produced conflicting results [39].

Fadaei et al. found that serum CTRP13 levels are independently correlated with BMI, insulin, HOMA-IR, HbA1c, and TNF-α [29]. They believe that CTRP13 is associated with the metabolic and inflammatory markers of diabetes. Reza Fadaei et al. first investigated the expression level of circulating CTRP12 in patients with CAD and its correlation with glucose metabolism. Their results demonstrated that circulating CTRP12 levels were decreased in patients with CAD and were negatively correlated with HOMA-IR, BMI, and TNF-α [40]. As a member of the adipokine superfamily, the CTRPs may play a crucial role in the onset and progression of T2DM macro-vasculopathy, which requires further exploration.

Circulating CTRPs levels and micro-vasculopathy

Diabetic micro-vasculopathy encompasses conditions, such as diabetic nephropathy (DN), diabetic retinopathy (DR), diabetic cardiomyopathy, diabetic neuropathy, and others [41]. In recent years, there have been reports in the literature highlighting variations in the CTRP family's changes in diabetic micro-vasculopathy. A study by Yan Z revealed a connection between CTRP3 deficiency and proliferative DR, as well as an inverse relationship between CTRP3 deficiency and vascular cell adhesion molecule-1 (VCAM-1) [42]. Asada et al. observed higher plasma CTRP9 levels in T2DM patients with CKD compared to those without CKD [26].

Another investigation revealed that 14 out of 28 DN patients had detectable levels of CTRP9 in their plasma. The disparity in urinary albumin–creatinine ratio between the group with and without CTRP9 detection was statistically significant [43]. In summary, CTRP9 has the potential to reflect the renal pathophysiology in T2DM patients. In addition, a study by Moradi's team in 2019 demonstrated that CTRP3 levels in the serum of DN patients were notably lower compared to those in the control group [44].

Du et al. investigated the association between CTRP12 and DN for the first time. They discovered that serum CTRP12 levels were significantly lower in both the T2DM group and the T2DM + DN group compared to the control group. Furthermore, the CTRP12 level in the T2DM + DN group was notably lower than that in the T2DM group, and was linked to the severity of renal insufficiency. In addition, the serum CTRP12 level in T2DM patients showed a negative correlation with the Duration of diabetes, blood urea nitrogen, uric acid, And 24-h urinary albumin excretion rate [45]. Furthermore, further research is required to investigate the correlation between circulating CTRPs levels and diabetic micro-vasculopathy.

Mechanism of CTRPs on vascular injury in T2DM

Oxidative stress

Oxidative stress plays a crucial role in the progression of diabetic cardiovascular and microvascular complications [46]. It is characterized as a metabolic condition stemming from an imbalance between the generation of oxygen free radicals and the body's ability to neutralize them with antioxidants [47]. VECs in diabetic patients are often harmed by oxidative stress. In addition, the excessive production of reactive oxygen species (ROS) by these cells is a critical factor in endothelial damage, leading to the disruption of endothelial junctions and an increase in vascular permeability, ultimately resulting in the development of both macrovascular and microvascular diseases [48].

Oxidized low-density lipoprotein (ox-LDL) acts as a stress signal involved in the development of atherosclerosis. According to Sun et al., CTRP9 aids in mitigating ox-LDL-induced damage to human umbilical vein endothelial cells (HUVECs) and can trigger the increase of antioxidant enzymes via the peroxisome proliferator-activated receptor co-activator1α (PGC1-α) adenosine monophosphate-activated protein kinase (AMPK) signaling pathway [18]. As a newly discovered cardiovascular protective factor, CTRP9 may have a beneficial effect on alleviating oxidative stress-induced injury in the large vascular endothelium in T2DM. In addition, Zhu et al. discovered that overexpression of CTRP13 diminishes palmitic acid (PA)-induced oxidative stress damage in the same type of cells And can also activate AMPK signaling while regulating the expression of downstream genes NADPH oxidase 1 (Nox1) and krppel-like factor (KLF)2 [49].

The primary early indications of DR include the decreased or vanishing of vascular wall cells, abnormal proliferation of capillary endothelial cells, thickening of the basement membrane, impairment of blood–retinal barrier function, retinal ischemia and hypoxia, leading to pathological new angiogenesis [50]. Fork head box O4 (FOXO4) is a prevalent transcription factor that has been reported to be involved in the regulation of resistance to oxidative stress in DR [51]. The signaling of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB) has been demonstrated to impact high glucose (HG) induced oxidative stress [52, 53].

Therefore, Zeng et al. investigated the oxidative stress mechanism of CTRP3 in DR. They discovered that CTRP3, which is downregulated by FOXO4, could mitigate oxidative damage in human retinal pericytes exposed to HG by modulating the Nrf2/NF-κB pathway. CTRP3 may have a protective role in HG-induced vascular injury [54].

Jian Zhang et al. showed that HG stimulation induces oxidative damage in retinal pigment epithelial cells, such as ARPE-19 cells. HG stimulation led to a significant increase in ROS production and malondialdehyde levels, as well as a decrease in superoxide dismutase activity in ARPE-19 cells. CTRP3 also alleviated HG-induced oxidative stress in ARPE-19 cells, reducing ROS levels and increasing superoxide dismutase activity. Overexpression of CTRP3 enhances activation of the Nrf2 heme oxygenase-1 (HO-1) pathway in HG-stimulated ARPE-19 cells, while Nrf2 knockdown can reverse CTRP3-mediated oxidative stress [55].

The decreased levels of reactive oxygen species (ROS) and malondialdehyde, and the increased activity of superoxide dismutase, suggested that overexpression of CTRP9 effectively reduced oxidative stress induced by high glucose. Furthermore, CTRP9 significantly promoted the activation of the AMPK/Nrf2 pathway in high glucose-treated retinal cells. Conversely, blocking AMPK or Nrf2 inhibited the protective effect of CTRP9 on high glucose-stimulated ARPE-19 cells. These findings indicate that CTRP9 exerts a protective effect on diabetic retinal cells, potentially through the activation of the AMPK/Nrf2 signaling pathway [56].

In addition, several studies have documented the correlation between CTRP members and Xu et al. studied the impact of CTRP6 on oxidative stress in mesangial cells (MCs) from DN patients. MCs are located in the middle of renal capillaries and play a crucial role in supporting and purifying the environment in the glomerulus. In DN, vascular lesions are primarily caused by inflammation, hemodynamic and metabolic disorders in glomeruli, and tubulointerstitial micro vessels [6]. The study revealed that CTRP6 (via Akt/NF-κB) exhibits an exacerbating effect on oxidative stress, which contrasts with the protective effect of CTRP9 and requires further research [57]. Further basic research is necessary to elucidate the mechanism by which CTRP affects T2DM vascular disease through the oxidative stress pathway.

According to the existing Literature, members 3, 9, And 13 demonstrated more significant protective effects, to some extent alleviating oxidative stress damage and slowing down the progression of diabetic vascular lesions. On the contrary, CTRP6 is very Likely to be An Antioxidant stress-promoting factor. Further basic research is needed to clarify the specific mechanism by which CTRP affects vascular diseases in type 2 diabetes through the oxidative stress pathway.

Inflammation

The inflammatory state is strongly associated with the development of vascular lesions in diabetes. Endothelial cell activation is a common feature of diabetes and leads to the expression of intracellular adhesion molecule-1 (ICAM-1), VCAM-1, and E-selectin. Soluble forms of VCAM-1 and ICAM-1 are released from activated endothelial cells and serve as markers of inflammation. These soluble factors stimulate leukocyte activation and chemotaxis to sites of tissue damage. Elevated levels of circulating VCAM-1, ICAM-1, and E-selectin are closely linked to vascular complications in human diabetes [58]. Moreover, NF-κB is a transcription factor that plays a crucial role in regulating diabetic complications [58]. Elevated blood sugar levels can result in excessive production of TNF-α and interleukin (IL)−1β, leading to NF-κB activation and subsequent inflammatory response [59]. The protein kinase B (AKT) endothelial nitric oxide synthase (eNOS) signaling pathway is closely associated with the development of hyperglycemia-induced endothelial dysfunction [60]. Wang et al. showed that CTRP3 decreased the mRNA levels of TNF-α, IL-1, IL-6, And monocyte chemotactic protein 1 (MCP-1) induced by HG in HUVECs through activation of the Akt–eNOS signaling pathway, thereby improving the inflammatory status of endothelial cells [61]. It has been discovered that CTRP9 is capable of suppressing macrophage inflammation and enhancing carotid plaque stability. In addition, CTRP9 intervention can mitigate TNF-induced endothelial inflammation [62], suggesting that certain CTRP members may impact the development of diabetic vasculopathy by altering the macrovascular inflammatory microenvironment. Furthermore, Schmid et al. conducted gene expression analysis in endothelial cells, including primary mouse endothelial cells, mouse endothelial cell lines, and HUVECs, and observed expression of CTRP3 mRNA under basal conditions. Exogenous administration of CTRP3 significantly inhibited lipopolysaccharide-induced VCAM-1 and ICAM-1 mRNA levels in endothelial cells, as well as the release of soluble ICAM-1 and VCAM-1 proteins [63].

Research indicates that the knockdown of CTRP6 led to a significant decrease in the production of TNF-α, IL-1, and IL-6 in HG-induced MCs. In addition, CTRP6 knockdown inhibited the activation of the Akt/NF-κB pathway in HG-induced MCs. CTRP6 overexpression had the opposite effect [57]. CTRP members play a role in inflammatory injury in DN. In DR, the early and any stage is characterized by an inflammatory response. Several proinflammatory molecules, such as MCP-1, IL-1, and TNF-α, are known to contribute to DR pathology. Li et al. discovered that TNF-α, IL-1, and MCP-1 were upregulated in db/db mice. CTRP9 has a significant protective anti-inflammatory effect by reducing the activation of TNF-α and the expression of MCP-1 protein in endothelial cells. Furthermore, studies have shown that CTRP9 has a clear protective anti-inflammatory effect by reducing the levels of MCP-1, VCAM-1, and ICAM-1 proteins in endothelial cells [50]. Thus, it can be inferred that CTRP9 may exert a protective function in diabetes-associated micro-vasculopathy. Yan et al.’s research yielded similar findings and indicated that CTRP3 can impede the expression of VCAM-1, with the inhibitory impact being contingent upon dosage and duration. Specifically, CTRP3's capacity to diminish VCAM-1 expression in human retinal microvascular endothelial cells (HRMECs) treated with high glucose and high lipid (HGHL) was attributed to its ability to activate the AMPK pathway [42]. CTRP3 may act as an anti-inflammatory mediator and play a protective role in diabetic micro-vasculopathy.

Members 3 And 9 exhibited a more pronounced inhibitory effect on inflammation. This inhibitory action effectively decelerated the progression of diabetic vascular lesions. Regarding CTRP6, it is highly probable that it persists as a negative influencer in the context of inflammation. However, further in-depth research is essential to corroborate this hypothesis. In addition, the roles of the other members in relation to inflammation remain to be comprehensively investigated.

Senescence

The pathogenesis of diabetic vascular injury is thought to be related to HG-induced premature senescence of endothelial cells [64]. Endothelial cell senescence is characterized by a permanent halt in cell growth and proliferation, which plays a significant role in the onset and progression of atherosclerotic lesions. Pathological studies have shown that in diabetic patients with macrovascular complications, senescent endothelial cells will accumulate in the subendothelial space and gradually form a phenotype, the senescence-associated secretory phenotype [65, 66]. Studies have indicated that CTRP9 has the ability to suppress endothelial cell aging by activating AMPK [67] [68]. Concurrently, it has been observed that KLF4 can be downregulated by AMPK, and this factor has been recognized as crucial in the maintenance of cellular senescence [69]. Wang et al. have demonstrated that CTRP9 is capable of inhibiting vascular aging in streptozocin-induced apolipoprotein E knockout mice. Subsequent in vitro studies have further revealed that CTRP9 suppresses endothelial cell senescence through AMPK activation and negative regulation of KLF4 [70]. CTRP members may be involved in the pathway of vascular aging in T2DM. Nonetheless, further research is necessary to explore this mechanism.

The protective effect of CTRP9 on blood vessels and its inhibitory action against senescence suggest that the CTRP family is also implicated in the process of vascular senescence in patients with T2DM. Future research should be conducted to further explore and elaborate on this underlying mechanism.

Apoptosis

Vascular endothelial cells act as the primary protective barrier of the vessel wall. Apoptosis of endothelial cells is a contributing factor to endothelial dysfunction and breakdown of the endothelial barrier. Studies have indicated that ox-LDL-induced apoptosis of endothelial cells enhances lipid deposition, migration of vascular smooth muscle cells, formation of foam cells, and development of atherosclerotic plaques. Findings from H. Sun et al. demonstrated that CTRP9 significantly mitigated apoptosis in HUVECs in the presence of ox-LDL [18], and has a certain promoting effect on the repair of significant injury to large vascular endothelium in T2DM. Growing evidence suggests that mitochondrial dysfunction is a key factor in endothelial injury and diabetic vasculopathy [71]. Our previous research revealed that the globular domain of CTRP5 triggers apoptosis in diabetic vascular endothelial cells through the NOX1-mediated mitochondrial pathway. Lowering circulating levels of CTRP5 may offer new approaches for preventing and treating diabetic vascular injury [34]. Zeng et al. demonstrated that CTRP3 inhibits apoptosis of human retinal pericytes exposed to high glucose [54].

The retinal pigment epithelium (RPE), located in the outer layer of the retina, plays a crucial role in converting light energy into electrical impulses and regulating vision [72]. In conditions of high blood sugar, excessive intracellular glucose flux can lead to damage in the retina, which appears to result from inflammation and apoptosis [73]. CTRP9 has the ability to prevent apoptosis in human retinal pigment epithelial cells when exposed to high glucose levels, reduce caspase-3 activity and Bax expression, and increase Bcl-2 expression [43]. The rate of apoptosis in ARPE-19 cells with elevated CTRP3 was significantly reduced. Moreover, the overexpression of CTRP3 increased Bcl-2 expression and decreased Bax expression [55]. The TUNEL assay demonstrated that treatment with PA induced apoptosis in HUVECs cells, while the upregulation of CTRP13 effectively counteracted the PA-induced apoptosis. Similarly, Western blot Analysis revealed a significant increase in the expression of Bax And cleaved-caspase 3 in PA-induced cells, as well as a decrease in Bcl-2 expression. Overexpression of CTRP13 reversed the expression levels of Bax, Bcl-2, And cleaved-caspase 3 [49].Recent studies suggest that certain CTRPs may be involved in the regulation of vascular lesions in T2DM through the apoptosis pathway. However, further research is necessary to elucidate the underlying mechanism.

Members 3, 9 And 13 still demonstrated a positive protective effect, reducing mitochondrial apoptosis in diabetic vascular cells And delaying the progression of atherosclerosis. However, member 5 could accelerate this process. Further research is necessary to elucidate the underlying mechanism.

Vascular vasodilatory dysfunction

Vascular endothelial dysfunction is characterized by reduced endothelium-dependent vasodilation, chronic inflammation, hyperpermeability, leukocyte adhesion, and cellular aging, serving as the initial stage of vascular disease and a crucial prognostic indicator for diabetic vascular complications [74]. It is a hallmark of diabetes, contributing to associated vascular complications. An important aspect of endothelial dysfunction is impaired vasodilation. Nitric oxide (NO), a vasoactive substance and potent vasodilator released by vascular endothelial cells, plays a role in multiple signaling pathways, dilates blood vessels, and thereby maintains normal endothelial function. It is generally believed to have a protective effect on blood vessels in diabetic patients [75]. Impaired NO bioactivity is closely correlated with endothelial dysfunction, with the primary event being the decreased eNOS activity or expression in endothelial cells and reduced NO production induced by hyperglycemia, leading to excessive production of superoxide anion. This impairs endothelium-dependent relaxation and triggers endothelial dysfunction [49, 76]. Numerous studies have reported the involvement of CTRP family members in the development of large vessel endothelial injury and diastolic dysfunction in T2DM to varying degrees. It has been observed that CTRP9 enhances AMPK/Akt/eNOS phosphorylation and NO production via adiponectin receptor-1. Knockdown of Akt had no effect on CTRP9-induced AMPK phosphorylation, but it suppressed eNOS phosphorylation and NO production. Incubation of vascular rings with AMPK inhibitors verified that CTRP9-induced vasodilation could also be abolished [16]. The study findings by Sun et al. also suggested that AMPK serves as a crucial upstream mediator in the improvement of vascular endothelial function by CTRP9. They found that CTRP9 prevented the inhibition of AMPK phosphorylation caused by ox-LDL. Furthermore, the suppression of AMPK negated the inhibitory impact of CTRP9 on ox-LDL-induced endothelial dysfunction [18]. Recent studies have indicated that PPAR activators upregulate eNOS expression primarily by stabilizing eNOS mRNA, thus protecting endothelial function. In addition, it has been found that GTP cyclohydrolase 1 (GCH1) expression is a key factor determining endothelial NOS regulation [77]. Wang et al. paid attention to it and carried out research. They first showed that CTRP13 supplementation rescued the impaired endothelium-dependent relaxation in db/db mouse aortas in vivo. In addition, they demonstrated through cellular experiments that CTRP13 could boost GCH1-dependent eNOS coupling at the transcriptional level via protein kinase A (PKA) and peroxisome proliferator-activated receptor (PPARα), leading to improved endothelial NO production and normalization of excessive ROS levels in endothelial cells [78]. In one study, PA induced a reduction in NO levels, along with a decrease in phosphorylation of eNOS (p-eNOS), compared to the control group, indicating endothelial dysfunction in HUVECs caused by PA. However, overexpression of CTRP13 resulted in increased NO levels and elevated p-eNOS levels, suggesting that CTRP13 could mitigate PA-induced endothelial cell dysfunction in HUVECs. Upregulation of CTRP13 activated AMPK signaling and regulated the expression of downstream genes NOX1P38 and KLF2 [49]. Liu et al. demonstrated that the enhanced expression of CTRP1 is involved in vascular endothelial hyperpermeability through the activation of vascular endothelial growth factor receptor 2 signaling in an autocrine/paracrine manner [79]. And it can be speculated that blocking CTRP1 can bring therapeutic effects on improving vascular endothelial barrier dysfunction in T2DM.

Furthermore, in comparison with the large and intermediate arteries, the smooth muscle layer of the microvascular wall has a relatively thin contractile and diastolic function. The microvascular endothelium exhibits poor contractile and diastolic function, making it susceptible to T2DM. Yan et al. demonstrated that the globular domain of CTRP3 activates AMPK and eNOS, leading to the stimulation of NO production in cultured HRMECs. This indicates that CTRP3 may have a protective role in diabetes-induced microvascular relaxation dysfunction through the AMPK–eNOS–NO signaling pathway [80]. Further studies are needed to explore the role of CTRP family in microvascular relaxation in T2DM.

Members 3, 9 And 13 still demonstrated a positive protective effect, improving the vascular dilation dysfunction of diabetes And delaying the progression of atherosclerosis. However, member 1 had the opposite effect. Further studies are needed to explore the role of CTRP family in microvascular relaxation in T2DM.

Tight junctions

The primary pathological change in DR is the dysfunction of endothelial cells, disruption of the blood–retinal barrier (BRB), and the development of new blood vessels. The BRB is composed of tight junctions formed by retinal vascular endothelial cells (inner BRB) and RPE cells (outer BRB) [81]. Vascular endothelial cells and tight junctions are the functional foundation of the BRB. Tight junction-associated proteins play a crucial role in the formation and maturation of the retinal vascular system, maintenance of vascular integrity, and preservation of the normal biological function of the retina. Yan et al. have reported that CTRP3 significantly increases AMPK phosphorylation and upregulates the levels of Occludin and Claudin-5 in human retinal microvascular endothelial cells. CTRP3 is an important adipokine that protects against high glucose high lipid-induced intraretinal blood–barrier damage [82]. In addition, another study found that overexpression of CTRP9 promotes the expression of tight junction proteins, such as zonula occludens-1 (ZO-1), Claudin-5, And Occludin 52. Overall, these findings provide new insights for future research into the mechanisms of CTRPs in diabetic vascular disease.

According to the existing Literature, members 3 And 9 play a stable protective role in diabetic vascular lesions. They can even enhance the tight junctions between vascular cells, strengthen the vascular endothelial structure, and delay the progression of atherosclerosis. In summary, these findings provide new insights for future research on the mechanism of CTRP in tight junctions in diabetic vascular diseases.

The AMPK pathway is a signaling pathway that plays a crucial regulatory role in cellular energy metabolism. Based on the existing Literature, the AMPK pathway has been frequently mentioned in the exploration of CTRPs. As their upstream targets, CTRPs can directly or indirectly activate AMPK. For instance, members 3, 9, And 13 can improve the function of vascular endothelial cells in T2DM And reduce inflammatory damage caused by oxidative stress, as well as promote vasodilation. Member 3 regulates the energy metabolism of cardiac cells by activating the AMPK pathway, improves myocardial ischemia–reperfusion injury, and delays cardiac cell aging. In addition, CTRP3 can activate the AMPK pathway in T2DM to increase the width of tight junctions and improve the permeability between vascular endothelial cells, and slow down the development of AS. These provide certain beneficial support for clinical diagnosis and treatment to a certain extent.

Conclusions

The pathogenesis of diabetic vasculopathy is complex. The levels of different CTRPs change in different vascular lesions, and they may participate in the development of diabetic vasculopathy through multiple pathways, such as oxidative stress, inflammation, aging, apoptosis, diastolic dysfunction and tight junction. This review will help us to further understand the relationship between the CTRPs family and diabetic vasculopathy.

However, this review has certain limitations: the CTRP family has 15 family members to date, but we have been collecting literature since its inception and have found that many of the CTRP members have not been involved in studies of diabetic vascular disease. The members that have been studied more comprehensively and in detail include CTRP1, CTRP3, CTRP6 and CTRP9. Second, current research mostly focuses on the role in in vitro cells, with relatively few animal experiments. Although this is strong evidence for the reliability and universality of the mechanism, it is undeniable that relying on cell-based studies (for example, HUVECs and ARPE-19) and sparse in vivo data may limit the applicability of research results to clinical diabetic vascular lesions. In addition, some CTRPs play a complex dual regulatory role in diabetes as well as its vascular complications, which may be related to the differences in the in vivo environment due to differences in BMI, disease duration, and the number and type of concomitant diseases.

As adipokines, it can be considered that certain CTRPs, especially CTRP1, CTRP3, CTRP6 and CTRP9, are closely related to diabetic vascular lesions. However, it should be noted that further comprehensive research is needed to confirm their combined effect.

Author contributions

Draft manuscript preparation: RS, GRZ, WTH; Search literature: JLG, YWZ,WYG,FW; Critical revision of the paper: JL, CR, YKZ; Final approval of the version to be published (the names of all authors must be listed): RS, RC, GRZ, JLG, YWZ, WTH, WYG, FW, YKZ, JL.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82000799) and Basic Research Program of Shanxi Province (Nos. 202303021211209, 202303021222335). Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (No. 2022L145).

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No datasets were generated or analysed during the current study.

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Competing interests

The authors declare that they have no competing interests.