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. Author manuscript; available in PMC: 2026 Apr 9.
Published in final edited form as: Curr Opin Physiol. 2025 Oct 14;46:100862. doi: 10.1016/j.cophys.2025.100862

Caveolin in extracellular vesicles: orchestrating interorgan communication in diabetes-associated cardiovascular disease☆

Zhijun Meng 1,2,*, Mary K Sewell-Loftin 3, Vinoy Thomas 4, Xinliang Ma 1, Yajing Wang 3
PMCID: PMC13061378  NIHMSID: NIHMS2145280  PMID: 41960196

Abstract

Small extracellular vesicles (sEVs) have been recognized as critical mediators of intercellular communication, impacting processes such as inflammation, tissue repair, and cardiovascular disease progression. Conventionally, research has focused on the general role of sEVs in mediating the signals among cell–cell communication without specifically considering the underlying molecular regulators.

However, recent insights highlight the emerging importance of Caveolin, a protein integral to the formation of caveolae, in the regulation of EV biogenesis and release, particularly exosomes. This review underscores the novel role of Caveolin in sEV in shaping interorgan communication via sEV-mediated signaling and how it alters the cardiovascular disease development via modulating multiple pathways. These causes of sEVs transport crucial signaling molecules, including small RNAs and proteins, capable of modulating disease progression positively or negatively.

Furthermore, we emphasize novel developments regarding Caveolin-1’s influence on diabetes-related cardiovascular pathologies and metabolic disturbances, specifically insulin secretion, insulin signaling, insulin resistance, oxidative stress, and diabetes-associated complications. By bridging traditional views with recent advancements, this review seeks to provide a comprehensive understanding of Caveolin-1’s potential as a therapeutic target in cardiovascular and metabolic disorders.

Introduction

Diabetes mellitus significantly increases the risk of cardiovascular diseases, leading to substantial clinical challenges. Traditionally, the pathogenesis of diabetic cardiovascular complications has been attributed to metabolic dysfunction, oxidative stress, and inflammation. However, emerging evidence underscores the importance of interorgan communication in mediating disease progression and response. This interorgan crosstalk involves the exchange of signaling molecules such as peptides, proteins, and metabolites between organs, coordinating essential cellular processes under both homeostatic and stress conditions.

Cells possess intrinsic defense mechanisms to maintain homeostasis and respond to stress, with interorgan communication being a pivotal component. This communication enables tissues to coordinate protective responses against systemic stressors and disease conditions. One key mediator of this interorgan dialogue is small extracellular vesicles (sEVs), which transport bioactive cargoes — including proteins, metabolites, and nucleic acids — between cells and organs. EVs play a crucial role in maintaining metabolic homeostasis and are involved in interorgan communication under both physiological and pathological conditions.

Central to the regulation of sEV-mediated interorgan communication are caveolae, specialized omega-shaped invaginations of the plasma membrane enriched with cholesterol, sphingolipids, and proteins of the caveolin family. Caveolae facilitate rapid and efficient communication by mediating the uptake and release of extracellular substances, including sEVs [1]. Highly abundant in adipocytes, endothelial cells, and cardiomyocytes, caveolae significantly influence cardiovascular health, with their dysfunction implicated in various pathological states [2], including diabetes-related cardiovascular diseases.

The objective of this review is to provide an updated and comprehensive analysis of the role of caveolae in cell defense mechanisms via sEVs in cardiovascular disease. By elucidating the molecular mechanisms linking caveolae in sEVs and cardiac health, we aim to provide a deeper understanding of the current research priorities and address specific challenges, thereby potentially guiding the development of novel therapeutic strategies for diabetic cardiovascular complications.

Why is caveolin vital in physiological cardiovascular events?

The cellular defense system plays a critical role in determining whether protective or adaptive responses are initiated within cells, relying heavily on the cell membrane as the frontline interface with the extracellular environment. Naturally occurring structures within the membrane, such as caveolae, significantly contribute to these selective and coordinated responses.

Caveolae consist of caveolins and cavins

Three Caveolin family members form the caveolae structure with special lipids [3]. Caveolin-1 and Caveolin-2 are mainly expressed on the surface of a variety of tissue cells, such as skeletal myoblasts, endothelial cells, adipose cells, and fibroblasts. Caveolin-3 is mainly expressed in differentiated skeletal muscle cells and myocardial cells. They lack the outer lobe of the plasma membrane and possess both N-terminal and C-terminal domains that face the cytoplasm. Caveolin-1 and Caveolin-3 shared 85% of their amino acid sequences (Figure 1). Cavins controls the formation of caveolae via interacting with caveolin [4]. Cavin3 mediates caveolae endocytosis and their intracellular transport [5]. Cavin4 is dispensable for caveolae formation in muscle cells and involved in the recruitment of caveolae-associated signaling proteins [6].

Figure 1.

Figure 1

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The overview of function and distribution in caveolin family. Caveolin family play important role in cellular function, such as signal transduction, lipid metabolism, endocytosis, and cytoprotection. Caveolin-1 and Caveolin-2 are mainly expressed on the surface of a variety of tissue cells, such as skeletal myoblasts, endothelial cells, adipose cells, and fibroblasts. Caveolin-3 is mainly expressed in differentiated skeletal muscle cells and myocardial cells.

Traditional view of caveolin in cardiovascular diseases

For decades, caveolae were considered to be a platform, caveolins interact with various signaling proteins through their N-termini, termed domain known as the caveolin-scaffolding domain (CSD), which interacts with many signaling proteins.

Ischemic preconditioning (PC) is the most effective way to protect the heart from ischemia-reperfusion injury. The underlying mechanisms are related to the well-coordination and orchestration of multiple intracellular signaling systems by PC, including Src tyrosine kinase, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), glycogen synthase kinase-3β, and protein kinase C (PKC) [7]. More importantly, these signaling and effector molecular systems either interact directly with the scaffolding domain (SD) of caveolin or localize directly to the caveolin [8]. In our recent study, we found that sevoflurane preconditioning (SF-PreCon) decreased MI/R injury in WT mice, but SF-PreCon failed to protect Cav3-knockout mice against MI/R injury. The mechanism is that Cyclooxygenase-2, a molecule upregulated by MI/R, can be significantly inhibited by SF-PreCon in a Cav3-dependent manner [9]. Meanwhile, another recent study result indicated that Cav3-centered signalsome (including IRβ and AdipoR1) is disassembled in prediabetic cardiomyocytes, blocking multiple cardioprotective signaling. Cav3 nitration at Tyr73 is a novel post-translational modification of a molecule critical in organizing transmembrane signaling, contributing to prediabetic cardiac injury [10]. Overall, these observations indicate that caveolins play a pivotal role in cardioprotection against ischemic injury, which was summarized in Figure 2a.

Figure 2.

Figure 2

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Traditional view of the signals in caveolin-mediated during the pathology of heart diseases. (a) The caveolin-mediated signals in MI/R injury. (b) The caveolin-mediated signals in cardiac hypertrophy. (c) The caveolin-mediated signals in AS. (d) The caveolin-mediated signals in macrovascular circulatory system. CaMKII, Calcium–calmodulin (CaM)dependent protein kinase II; GSK-3β, glycogen synthase kinase-3β; COX2, Cyclooxygenase-2; ERK1/2, Extracellular regulated protein kinases; JNK, c-Jun N-terminal Kinase.

Accumulating data have demonstrated that Caveolae influence the process of cardiac hypertrophy [11]. This notion has been supported with clinical data by mutations in Cav3 (Thr63Ser, Thr78Met, Ala46Thr, and the deletion of Phe96) associated with cardiac hypertrophy in human patients [12]. The mechanism underlying caveolae-provoked cardiac hypertrophy is closely related to caveolin’s characteristics. Downregulation of growth signals (over-activation of p42/44 Mitogen-Activated Protein Kinase and up-regulation of endothelial nitric oxide synthase (eNOS) activity and nitrification stress [13]) is the most likely cause of growth inhibition of cardiomyocytes induced by caveolin-1 expression [14]. Pathological cardiac hypertrophy is characterized by subcellular remodeling of the ventricular myocyte, accompanied by decreased Cav3, altered Ca2+ cycling, increased PKC expression, and over-activation of calcineurin/nuclear factor of activated T cell signaling [15] (Figure 2b).

Endothelial Caveolin-1 participates in the process of atherosclerosis (AS) development. eNOS is the canonical signaling enzyme associated with caveolae. eNOS is sequestered in its inactive state and inhibits eNOS activity [16] by interacting with Cav1. Caveolin also plays an inflammatory regulatory role by regulating inflammatory signaling pathways, including Nuclear Factor kappa-B, Mitogen-Activated Protein Kinase [17], and Reactive Oxygen Species production through NADPH oxidase by regulating oxidative stress and oxLDL-induced vascular cell senescence [18]. Likewise, Cav1 was recently reported to be involved in the development of AS by reducing PI3K/Akt/JNK-mediated activation of autophagy [19]. In addition, it has been reported that Cav1 is negatively correlated with autophagy-related protein 5 and beclin-1 [20]. These results suggest that caveolin-1 is associated with AS, which contributes to establishing a new treatment strategy in order to slow the progression of AS. We summarized these in Figure 2c.

In addition to the macrovascular circulatory system, the role of Caveolae and Caveolins in microcirculation cannot be neglected. Endothelium-specific expression of caveolin-1 modulates microvascular permeability and angiogenesis in two modalities [21]. One model is as structural proteins involved in caveolae formation and endocytosis; the other model is to negatively regulate the paracellular pathway as a tonic inhibitor of eNOS activity. eNOS regulates microvascular hyperpermeability in vivo [22]. Moreover, reduced caveolin-1, along with decreased expression of tight junction-associated proteins occludin and zonula occludens-1, after stimulation of brain microvascular endothelial cells with the chemokine CCL2 [22]. Studies have shown that endothelium-dependent hyperpolarization (EDH), rather than NO, plays a dominant role in small resistance vessels. EDH-mediated responses of coronary microcirculation were decreased in endothelium-specific Cav1-knockout (eCav1-KO) mice [23]. Also, in human coronary arterioles, H2O2 produced by endothelial cells plays an important role in flow-induced vasodilation [24]. Thus, it was indicated that caveolin is a promising target for ameliorating microvascular dysfunction, and the associated signaling was summarized in Figure 2d.

Multiple cell types express caveolin, and as a result, caveolin knockout (KO) mice exhibit varied effects across different organs. Li et al. have found that the Cav1-KO mice exhibited more severe hepatic steatosis upon High-Fat Diet (HFD) intake, which is consistent with Cav1 repression in the livers of HFD-induced mice [25]. Another study found that Cav1-KO mice were resistant to weight gain when fed with HFD, although they exhibited high serum cholesterol and Free Fatty Acids levels, impaired glucose tolerance, and insulin resistance. Cav1-KO mice on an HFD showed an adaptive response in their pancreatic beta cells and exhibited a significant decrease in beta cell apoptosis in their islets compared to Wild Type (WT) mice. These findings suggest that Cav1-KO mice adapted better to an HFD despite their altered metabolic state, which may, at least in part, be due to reduced beta cell damage [26]. In addition, Willière et al. found that a decrease in activating phosphorylation of the Na-Cl cotransporter (NCC) in the distal convoluted tubule was observed in Cav1-KO compared to WT kidneys. This suggests that renal caveolae help to conserve water and electrolytes via modulation of the function of the NCC [27]. However, the roles of caveolins are not yet fully understood, necessitating further investigation to clarify their functions and mechanisms of action.

A big miss for the mechanism is caveolin associated with exosomes

The role of caveolin regulates extracellular vesicle packaging, uptake, and cellular communication

Accumulating evidence showed that Caveolin plays an essential role in the biogenesis of extracellular vesicles (EVs). EV membranes are rich in cholesterol and sphingolipids, a characteristic shared with caveolae membranes and membrane raft components [28].

Recently, it was found that Cav1 is also a kind of secreted protein that can be incorporated into exosomes and plays an important role in determining cargo composition [29]. EV cargo can be determined from the cytoplasm during biogenesis, or by the sorting mechanism of regulation [30], although the mechanisms are yet to be elucidated.

A range of molecules, such as Flotillin-1, Cav1, and Dynamin-2 (Dyn-2), have been identified as receptors that mediate EV intake in various cell types [31]. After internalization through clathrin- and caveolin-mediated endocytosis, phagocytosis, and/or direct fusion, EVs can deliver their cargos into the cytosol, which changes the physiological state of the receptor cells [32]. Cholesterol levels increased with the attachment of CSDs to the plasma membrane, and Dyn-2 activity enables assembly and expansion of caveolar endocytic vesicles [33]. Blockade of Dyn-2 significantly reduced EV internalization, suggesting that caveolae-mediated endocytosis plays a role in vesicle uptake. Specific knockdown of Cav1 gene resulted in decreased caveolin-1 protein and impaired EVs uptake [34]. Moreover, Kou et al. found that Fas binds to Fas-associated phosphatase–1 and Cav1 and activates the common soluble N-ethylmaleimide–sensitive factor (NSF) attachment protein receptor (SNARE)–mediated membrane fusion mechanism to release sEVs in Mesenchymal Stem Cells [35]. However, these uptake mechanisms are not consistent and depend largely on the cellular source of the EV and the recipient cell type.

Recently, researchers have begun to explore the role of EVs as modulators of the cross-talk in cellular communications. Many cell types secrete EVs rich in protein and miRNA that have complex effects on recipient cells. Crewe et al. found that EVs mediate intercellular communication between adipocytes and stromal vascular cells. After successful ablation of the Cav1 gene, Cav1 protein remained readily detectable in adipocytes. This was found to be a consequence of sEV-mediated trafficking of Cav1 from adjacent endothelial cells to adipocytes [36]. sEVs secreted by other cells (such as macrophages or stem cells) can also produce significant systemic effects after injection into mice, such as changes in systemic insulin sensitivity, glucose tolerance, and inflammation, which provides a new therapeutic approach for the treatment of obesity and type 2 diabetes [37]. Cav1 has also been reported to serve as a mediator of crosstalk among organs. Lee et al. described that Cav1 is present and augmented in lung epithelial cell-derived EVs after exposure to hyperoxia, and they found that Cav1 deletion resulted in decreased expression of hnRNPA2B1 in EVs in response to hyperoxia [38]. Additionally, Cav1 has been identified in populations of miRNA-rich EVs derived from lung epithelial cells [39]. Another recent research found that fatty acids (FA) induce CD36-dependent phosphorylation of Cav1 and ceramide production, and these effects are associated with caveolae budding to form EVs (containing FA, CD36, Cav1, and ceramides), which are then released at the basolateral membrane and deliver FAs to tissue cells [40]. Additionally, research found that mice with adipocyte-specific ablation of the Cav1 gene, which were fed HFD, exhibit significant adipose tissue inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. Interestingly, Injection of control mice with AT-sEVs from ad-Cav1KO mice propagates the phenotype of adipose tissue to the liver [41].

However, the function of Cav1 in the recipient cells is more controversial, because in some cases its presence favors internalization [34], and in other cases it delays exosome internalization [42]. In summary, the role of Cav1 in EVs is interesting and still needs more exploration, which we summarized in Figure 3.

Figure 3.

Figure 3

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The role of Caveolin regulates EV packaging, uptake, and cellular communication. Caveolin play an essential role in the biogenesis of exosomes package. Exosomes membranes are enriched in cholesterol and sphingolipids. After internalization through clathrin- and caveolin-mediated endocytosis, phagocytosis, and/or direct fusion, EVs are able to deliver their cargos into cytosol, and thereby modify the physiological states of recipient cells.

Will caveolins-mediated extracellular vesicles be the main player in cardiovascular disease?

Cav1, a major component of EVs, is involved in various protein trafficking pathways. It has generally been accepted that caveolin-dependent endocytosis contributes to the uptake of extracellular substances; meanwhile, caveolin also takes part in the excretion of intracellular materials, resulting in the formation of an EV, which is the main player in cardiovascular disease. Numerous studies revealed that EVs, especially stem cell-derived EVs, exerted therapeutic efficacy on Myocardial Infarction (MI). Bone marrow mesenchymal stem cells-secreted EVs (BMSC-EVs) are protected against MI by carrying proteins. mBMSC-EVs mitigate myocardial fibrosis in MI mice by delivering the Cav1 protein, inhibiting the TGF-β1/SMAD2/c-JUN pathway. BMSC-EVs delivered Cav1 into hypoxia-exposed cardiac fibroblasts (CFs) to repress fibrosis and apoptosis of CFs, accompanied by downregulated α-SMA, Collagen I, TNF-α, and IL-1β [43]. Previous studies have also shown the direct involvement of Cav1 protein in CFs, suggesting that Cav1 protein may exert its influence on myocardial fibrosis after myocardial infarction [44]. Another study has shown that CD44 mediated the activation of the FGFR2 signaling pathway as well as the cav1-dependent uptake of exosomes in vascular endothelial cells, which impacts biogenesis and proangiogenic function of plasma exosomes post-MI [45]. Sun et al. found that the interaction between hnRNPA2B1 and Cav1 is upregulated in Endothelial Cells when exposed to Low-intensity pulsed ultrasound (LIPUS). Moreover, LIPUS induces miR-99a trafficking into EVs by promoting nuclear translocation of hnRNPA2B1 and interacting with caveolin-1 to protect against inflammatory dilated cardiomyopathy (iDCM) development [46]. Taken together, these findings were summarized in Figure 4. Obviously, the role of Cav1-mediated EVs in cardiovascular disease is still ongoing research, and it is believed that their role will be better revealed in the future.

Figure 4.

Figure 4

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Imbalanced Caveolin-mediated EV signals are involved in cardiovascular disease and vascular disorders. Excretion of intracellular materials result in the formation of an EV, which participate in cellular biofunction, including fibrosis inhibition, biogenesis, and inflammation in cardiovascular disease and calcification in vascular disease.

Imbalanced caveolin-mediated extracellular vesicle signals involve vascular disorders

The Endothelial cells play a crucial role in regulating vascular function by regulating vascular tone, inflammation, oxidative stress, and hemodynamics. Cav1 is a major phenotype distributed in endothelial cells and regulates endothelium homeostasis. Previous studies reported that calcifying vascular smooth muscle cells (VSMCs) release Cav1-enriched EVs, and Cav1 knockdown abrogates calcification, which indicated a key role for Cav1 in the development of EVs that mediate vascular calcification [47]. Nik et al. further found that Cav1 plays a major role in calcifying EVs biogenesis in VSMCs. Epidermal growth factor receptor (EGFR) colocalizes with and inhibition modulates Cav1, which hinders calcifying EV formation [48]. Another study found that mechanical stretch alters Cav1 trafficking and EV release, and the released EVs have elevated mineralization potential [49]. Taken together, these findings were summarized in Figure 4.

Caveolin and extracellular vesicles, a culprit or victim in diabetes?

Caveolin and extracellular vesicles in diabetes

The role of Caveolae and Caveolins in multiple disorders is in great debate, and even complex in diabetic conditions. As a signaling transduction platform and broad distributions, fully addressing the specific role of caveolae and caveolins in one specific disease is challenging.

Several changes regarding Caveolins have been reported in obesity or diabetes. Cav1 expression is increased in the adipose tissue of obese patients, which may be due to increased transport of FAs to the plasma membrane [50]. Increased Cav1 is associated with cell cycle arrest in diabetes. This is because Cav1 expression increases and caveolae sequester Sirt1, which leads to the release of FOXO3 and cell cycle arrest [51]. Under physiological conditions, Sirt1 deacetylates forkhead box protein O3 (FOXO3), which attenuates FOXO-induced apoptosis and stops FOXO-p21-dependent cell cycle arrest [52]. Interestingly, FOXO3 directly stimulated Cav1 gene transcription in a cell cycle-independent manner; as a result, the three factors Cav1, Sirt1, and FOXO3 regulate cell cycle arrest in the feedback loop [53].

Cav1 can also be regulated by different microRNAs in diabetes. Studies have shown that miR-124a activates Cav1 in podocytes, miR-375 downregulates Cav1 gene expression [54], and miR-204 can target Cav1 mRNA and reduce its expression in endothelial cells. Trajkovski et al. identified Cav1 as a target gene of miR103 and miR107. Their inactivation upregulates Cav1 in adipocytes, thereby improving insulin receptor maintenance, enhancing insulin signaling, improving glucose uptake, and shrinking adipocyte size. Therefore, miR103/107 affected insulin sensitivity by downregulating elevated Cav1, suggesting that it may be a target for the treatment of T2DM [55].

In our recent study, we found that sEV may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury. This study demonstrates that miR-130b-3p is the most important molecule mediating diabetic adipocyte sEV proapoptotic effect [56]. Meanwhile, another study from our lab also identified the close relationship between adipocytes and cardiomyocytes through sEV. The study demonstrates for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched sEVs [57].

Taken together, these findings were summarized in Figure 5. A large number of studies linking caveolin to diabetes have great potential to drive proper future research in this area, leading to clinical translation.

Figure 5.

Figure 5

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Dysregulated Caveolae and Caveolin-1 play a role in diabetes and lead to metabolic dysfunction. Altered Caveolin-1 is associated with cell cycle arrest, vasodilation dysfunction, and metabolic dysfunction in diabetes. Also, sEVs may mediate pathological communication between diabetic adipocytes and cardiomyocytes through miR-130-3p and miR-23-27-24 cluster.

Conclusion and perspectives

In the past decade, many new scientific discoveries have been made about how caveolin regulates various aspects of the cardiovascular system. We now know that caveolin is not only a structural protein but also a key component of pro-survival and many other cellular regulatory pathways. The potential role of caveolin in cardiovascular physiology became evident by the discovery of Cav1KO, Cav3KO mice, and double KO mice with a cardiomyopathy phenotype. Caveolin can affect the signal transduction process through a variety of mechanisms; it helps organize the cell surface, regulates dynamic cell membrane trafficking in and out of the plasma membrane, and can affect signaling by altering lipid composition. Although the specific mechanism of action of caveolin is not very well understood, experimental evidence suggests that caveolin plays a dominant role in pulmonary hypertension, AS, cardiac hypertrophy, ischemic injury, and other different cardiac functions. A deeper understanding of its role in EV-mediated interorgan communication is essential, particularly in the context of diabetes-associated multiorgan dysfunction, before therapeutic strategies can be effectively developed and translated. The pathogenic role of the caveolin protein is an emerging field. The role of the alveolus is still a mystery. Given its multiple roles, caveolin has the potential to be an ideal target for future therapeutic agents if effectively and precisely targeted, but validation studies in large animal models and humans are needed.

Acknowledgements

The figures in this review were created using Biorender at https://app.biorender.com/ and Figdraw at https://www.figdraw.com/. We also acknowledge the outstanding contributions of Dr. Zhijun Meng, whose return to Shanxi Medical University in 2023 has significantly advanced our understanding in this field (Fund Program for the Scientific Activities of Selected Returned Overseas Professionals in Shanxi Province, Grant no. 20230054 and Research Project Supported by Shanxi Scholarship Council of China, Grant no. 2023-181).

Funding support

This work was supported by awards from the National Institutes of Health (HL096686, Ma/Wang, MPI; HL-123404, Ma; HL158612, HL157495 and HL173090, Wang) and the American Heart Association (24TPA1293530, Wang). UAB SOE innovation fellow award (Tan) and innovation fellowship support from the School of Engineering at the University of Alabama at Birmingham.

Abbreviations

LRs

lipid rafts

ERK1/2

extracellular signal-regulated kinase 1 and 2

CSD

caveolin-scaffolding domain

SFD

scaffolding domain

IR

insulin receptor

IRS1

insulin receptor substrate 1

IVs

internal vesicles

sEVs

small extracellular vesicles

PI3K

phosphatidylinositol 3-kinase

Akt

protein kinase B

PKC

protein kinase C

AS

atherosclerosis

PAH

pulmonary arterial hypertension

ZO-1

zonula occludens-1

Footnotes

Declaration of Competing Interest

All authors have read and approved the submission of the manuscript, and this review has not been published and is not being considered for publication elsewhere in whole or in part in any language. There is no other work in preparation, submitted, in the press, or published from our laboratory which overlaps with this paper. Furthermore, there are no financial or other relations that could lead to a conflict of interest.

Data Availability

Data will be made available on request.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest

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