Calcific aortic valve disease: can targeting endothelial-mesenchymal transition be a new alternative to surgery?—a narrative review

Introduction

Calcific aortic valve disease (CAVD) is one of the most common cardiovascular diseases in the elderly population, with high morbidity and mortality. The prevalence of CAVD reaches 1% to 2% in people over 65 years of age and up to 12% in people over 75 years of age (1). Globally, more than 100,000 people die from the disease each year, and the burden of disease due to CAVD is particularly significant in high-income countries (2). With the aging of the global population and increasing average life expectancy, the prevalence of CAVD is expected to double by 2050, making it a major public health challenge (3). However, there is currently no effective pharmacologic treatment for CAVD, and surgical valve replacement, including surgical replacement and transcatheter aortic valve replacement (TAVR), remains the only treatment option (4). While this treatment modality improves patient symptoms and quality of survival, it is accompanied by surgical risks, limited valve durability, and postoperative complications (3). Therefore, an in-depth understanding of the pathogenesis of CAVD, searching for new therapeutic targets, and developing non-invasive treatments have become important topics in medical research.

Although CAVD shares several risk factors and pathological features with atherosclerosis, pharmacologic therapies that are effective in vascular diseases have failed to show similar benefits in CAVD. Large-scale clinical trials with statins, RAAS inhibitors, and even Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have not significantly slowed the progression of valvular calcification or improved clinical outcomes (5,6). These findings indicate that conventional lipid-lowering and anti-inflammatory approaches are insufficient to modify valve-specific disease mechanisms. Therefore, identifying novel pathogenic pathways has become essential for developing non-invasive therapeutic alternatives to surgery.

CAVD is a complex, multifactorial disease driven by inflammatory, immune, and metabolic pathways. Innate immune cells, particularly macrophages, contribute to the progression of CAVD through paracrine signaling with valve interstitial cells (VICs), promoting inflammation and calcification (7). In addition, lipid metabolism, particularly lipoprotein(a) [Lp(a)] and autotaxin, plays a key role in CAVD by activating lysophosphatidic acid (LysoPA) signaling, which further accelerates inflammation and calcification of the valve (8). Recent studies have also highlighted the similarity between CAVD and atherosclerotic cardiovascular diseases (ASCVD), in which innate immune activation via nuclear factor-kappa B (NF-κB) signaling and the involvement of adaptive immune responses contribute to the disease progression (9,10). These findings emphasize the need for a comprehensive understanding of CAVD that integrates endothelial-mesenchymal transition (EndMT) with other parallel pathogenic mechanisms, offering potential new targets for non-invasive treatment strategies (Figure 1).

Figure 1 EndMT-associated mechanisms and therapeutic targets in CAVD. (A) Valve anatomy. Tricuspid aortic valve structure is illustrated, showing the RCC, LCC, and NCC, together with the endothelial monolayer on the surface of valve leaflets and the cross-sectional organization of vascular endothelial cells. (B) EndMT main pathway. Disturbed shear stress, extracellular matrix cues, and inflammatory stimulation activate TGF-β/Smad, ERK1/2, and NF-κB pathways, promoting endothelial cells to undergo EndMT and transform into mesenchymal-like cells, characterized by increased α-SMA and vimentin expression. (C) Therapeutic targets. Upstream interventions targeting shear stress and inflammation, core pathway inhibitors (including TGF-β, Notch, and Wnt signaling), and downstream anti-fibrotic strategies offer potential therapeutic approaches to modulate EndMT and prevent CAVD progression. AGE, advanced glycosylation end product; CAVD, calcific aortic valve disease; ECM, extracellular matrix; EndMT, endothelial-mesenchymal transition; ERK1/2, extracellular signal-regulated kinase 1/2; LCC, left coronary cusp; NCC, non-coronary cusp; NF-κB, nuclear factor kappa B; RCC, right coronary cusp; TGF-β/1, transforming growth factor β/1; VEC, valve endothelial cell; α-SMA, α-smooth muscle actin.

This review explores how EndMT, in combination with other key mechanisms such as immune activation and lipid metabolism, drives the progression of CAVD. By understanding these complex interactions, the review identifies potential therapeutic targets for early, non-invasive interventions in the management of CAVD. We present this article in accordance with the Narrative Review reporting checklist (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-373/rc).

Methods

A comprehensive literature search was conducted to identify studies focusing on EndMT in patients with aortic valve stenosis (Table 1).

Pathogenesis of CAVD

Valve anatomy and cellular composition

The aortic valve is a crucial component of the structure of the heart, of which its primary function is to ensure unidirectional flow of blood during systole and diastole. The normal aortic valve consists of three leaflets, with each leaflet divided into three layers: the fibrous, ventricular, and spongy layers (11). The fibrous layer is located on the aortic side and is rich in type I collagen fibers, which provide structural strength and resistance to tension of the valve leaflets; the ventricular layer is located on the outflow tract side of the left ventricle and is rich in elastin, which imparts good elasticity and flexibility to the valve; and the spongy layer is located in the middle and is rich in glycosaminoglycans (GAGs) and proteoglycans, which serve as a cushion against pressure (12). These structures act synergistically in the long-term high mechanical stress environment of the valve to ensure valve stability and long-lasting durability. The cellular composition of the valve consists mainly of VICs and valve endothelial cells (VECs). The VIC exists mainly as a resting fibroblast phenotype in the normal state, whereas it may be transformed into myofibroblasts or osteoblast-like cells that participate in the fibrotic and calcific processes of the valve in the pathological state (12). Together, these anatomical and cytological features maintain normal valve function, whereas any alteration in structural or cellular composition may lead to pathologic changes, such as the onset and progression of CAVD. In single-cell RNA sequencing studies, aortic VEC differed from arterial endothelial cells (AEC) in their transcriptomes. VEC exhibited gene expression profiles associated with fibrosis and calcification, particularly on the fibrous side, whereas AEC primarily maintained vascular homeostasis. This specific transcriptional profile of VEC may be implicated in the development of CAVD. These differences suggest that VECs are unique in their transcriptional regulation and may be potential therapeutic targets against CAVD (13).

Pathologic evolution: from fibrosis to calcification

CAVD is a slowly progressive degenerative disease that develops throughout the course of the disease from early aortic atherosclerosis to advanced calcific aortic stenosis. In the early stages of the disease, there is progressive thickening of the aortic valve leaflets with localized mild fibrosis and inflammatory cell infiltration, but hemodynamics are not yet significantly impaired (11). As the disease progresses, VIC gradually transforms into osteoblast-like cells that express osteogenic markers such as bone morphogenetic protein 2 (BMP2), alkaline phosphatase (ALP), and runt-associated transcription factor 2 (RUNX2), which are involved in the calcification process (14,15). In addition, amyloid deposition has been found to potentially amplify the inflammatory cycle, further accelerating the calcification process in the valve (16). In advanced stages, significant calcification and stiffening of the valve leaflets occurs and the valve opening is restricted, leading to left ventricular outflow tract obstruction and ultimately myocardial hypertrophy, heart failure, and even death (Figure 2) (11). Although surgery and transcatheter valve replacement are currently the only effective treatments, interventions targeting the early stages of CAVD may represent a critical window for future therapy (17).

Figure 2 Progression of calcific aortic valve disease. (A) Early aortic valve thickening. (B) VIC-to-osteoblast transition. (C) Advanced aortic valve calcification. ALP, alkaline phosphatase; BMP2, bone morphogenetic protein 2; RUNX2, runt-associated transcription factor 2; VIC, valve interstitial cell.

EndMT: a central mechanism of CAVD

Definition and molecular characterization of EndMT

EndMT is a common cell biological phenomenon in developmental, reparative and pathological states. EndMT is a cellular transdifferentiation process in which the endothelial cell phenotype changes to a mesenchymal phenotype. This complex biological process involves the gradual loss by endothelial cells of their specific endothelial hallmarks, such as tight junctions and vascular stability properties, while acquiring the migratory and invasive characteristics of mesenchymal cells (18). EndMT acts through the regulation of multiple signaling pathways, with members of the transforming growth factor-β (TGF-β) superfamily acting as core signaling molecules that play a key role in the regulation of endothelial cells (19). These transcription factors further trigger a series of signaling networks that culminate in the transformation of the endothelial to mesenchymal phenotype (20,21). EndMT is not only critical for organ formation and vascular sculpting during embryonic development, but is also involved in a wide range of pathological processes that such as fibrosis, inflammation, malignancy and vascular disease.

Core signaling pathways regulating EndMT

The role of TGF-β, Notch, and Snail signaling pathways in EndMT has been highlighted in several studies. TGF-β signaling promotes fibrosis by inducing lactylation of Snail1 (22). The Notch1 pathway also regulates EndMT through mitochondrial metabolism: the Notch1 intracellular domain activates oxidative phosphorylation and pyruvate dehydrogenase, whereas mutations (e.g., in tetralogy of Fallot) reduce mitochondrial localization and enzyme activity, underscoring its importance in cardiac development. In mice, Notch1 haploinsufficiency increased susceptibility to homocysteine-induced heart disease, which was alleviated by dichloroacetic acid, suggesting Notch1 as a potential therapeutic target (23).

While TGF-β and Notch remain central, other pathways such as NF-κB and DNA methyltransferase 1 (DNMT1) are also involved (24,25). Increasing attention has focused on cellular metabolism and epigenetics. Glycolysis-derived lactate promotes EndMT by inducing pyruvate kinase M2 (PKM2) lactylation, which facilitates Twist1 nuclear translocation and activates TGF-β1/Smad2 signaling. Endothelium-specific PKM2 deletion reduces lactate accumulation, alleviates ischemia-induced fibrosis, and highlights PKM2 lactylation as a critical regulator (26,27).

EndMT contributes to diverse pathological processes, including vascular disease, fibrosis, tumors, and neurological disorders. In atherosclerosis, EndMT accelerates vascular fibrosis and calcification, partly via ASF1A/P300 co-regulation of SNAI1 (28), or through progerin-mediated dysfunction in Hutchinson-Gilford syndrome involving TGF-β1/Smad3 (29). Mechanical stress also promotes EndMT through the Alk5-Shc pathway, emphasizing its role in vascular pathology (30). Thus, modulation of these pathways, particularly TGF-β, represents a therapeutic strategy for atherosclerosis (31,32).

EndMT also drives fibrosis in the heart and other organs, though its exact contribution to cardiac fibrosis remains debated. It may exacerbate HFpEF by generating fibroblast-like cells; ubiquitin-specific protease 7 (USP7), for example, promotes EndMT via SMAD3 deubiquitination, while its inhibition reduces fibrosis in HFpEF models (33). EndMT worsens post-myocardial infarction fibrosis and cardiac insufficiency (34). Conversely, Sox9 deletion reduces EndMT and accelerates wound healing, indicating therapeutic potential (35). Other protective interventions include Icariin, which inhibits ROS and autophagy dysregulation to attenuate perivascular fibrosis (36), and inhibition of Adora2a, which suppresses EndMT-driven subretinal fibrosis in neovascular age-related macular degeneration (37).

Importantly, EndMT is not only linked to fibrosis but also directly drives the calcification of aortic valves. During EndMT, VEC gradually lose endothelial markers (VE-cadherin, CD31) and acquire osteoblast-like features characterized by the expression of α-smooth muscle actin (α-SMA), RUNX2, and BMP2. Activation of the TGF-β/Smad2/3 pathway induces osteogenic differentiation programs, while PKM2 lactylation promotes Twist1 activation, which in turn accelerates the transcription of calcification-related genes. Similarly, alterations in Notch1 signaling and mitochondrial metabolism facilitate the metabolic reprogramming required for osteoblastic conversion. In addition, NF-κB-mediated inflammatory signaling enhances the expression of osteogenic markers such as RUNX2 and ALP, further amplifying calcification. Together, these mechanisms illustrate that EndMT provides a direct cellular and molecular link between endothelial dysfunction, fibrosis, and the osteogenic transition that underlies valvular calcification.

The role of EndMT in the pathologic process of CAVD

In CAVD, EndMT is considered to be one of the drivers of the valvular calcification process. VECs gradually lose their endothelial cell properties during EndMT and acquire the function of osteoblast-like mesenchymal stromal cells, which ultimately form calcified foci and drive the progression of CAVD pathology. This transformation process is regulated by a variety of factors, including shear stress, changes in extracellular matrix (ECM) composition, and the inflammatory microenvironment (38).

Shear stress: a mechanistic modulator of EndMT

In healthy aortic valves, stable shear stress regulates the Smad2/3 signaling pathway through the TGF-β receptor ALK5 to maintain endothelial cell homeostasis. However, in turbulent flow [e.g., low-magnitude multidirectional flow (LMMF)], TGF-β1 signaling is upregulated, and endothelial cells activate and undergo EndMT (39). Different types of shear stress differentially regulate EndMT. In arteries, laminar shear stress contributes to endothelial cell stability, whereas oscillatory flow may lead to endothelial cell dysfunction and activation of the EndMT process. Particularly in aortic valves, disturbances in shear stress, especially LMMF, are one of the key factors promoting EndMT, which may accelerate the formation of calcified nodules by promoting the activation and transformation of endothelial cells into osteoblast-like mesenchymal stromal cells. Deng et al. found that the advanced glycosylation end product (AGE) inhibitor aminoguanidine attenuates aortic flow velocity by upregulating, via the AGEs-RAGE axis, TGF-β1 and BMPR2 expression, significantly promoting EndMT, facilitating the transformation of endothelial cells into osteoblast-like mesenchymal cells, and accelerating the formation of calcified nodules via the osteogenic key transcription factor (RUNX2) (40). The sustained accumulation of AGEs not only serves as an initiating signal for EndMT but also plays a central role in the maintenance and exacerbation of valvular calcification. This finding reveals how shear stress disturbances directly contribute to the progression of CAVD by converting mechanical stimuli into pathologic calcification signals via EndMT.

Altered ECM composition: a microenvironmental trigger for EndMT

In CAVD, the ECM composition and structure undergo significant changes and become an important microenvironmental factor that penalizes EndMT. Bramsen et al. found that GAGs such as chondroitin sulfate (CS) and hyaluronic acid (HA) were abnormally enriched in the fibrous layer of diseased valves (41). CS significantly induces EndMT and directly enhances matrix mineralization, accelerating the formation of calcified lesions. In contrast, HA did not directly lead to matrix mineralization, although it similarly promoted EndMT phenotypic features (e.g., high expression of α-SMA and cell invasive capacity). This suggests that different types of GAG may differentially affect EndMT with the calcification process through specific signaling pathways (42). In addition, abnormally distributed GAG components can weaken endothelial cell-matrix connections and activate the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, further promoting EndMT. Blockade of the ERK1/2 pathway significantly reduced the expression of EndMT and calcification markers (38,42). These findings suggest that pathological changes in ECM are not only the result of CAVD lesions, but also an important driving force directly involved in the pathologic calcification process by inducing EndMT.

Exposure to inflammatory conditions: inflammatory activators of EndMT

Inflammation is one of the core drivers of CAVD development and progression, and EndMT plays a bridging role in this process. The NF-κB signaling pathway, as a key inflammatory regulatory pathway, plays an important role in EndMT induction (43-45). In the inflammatory state, NF-κB signaling is activated, which promotes the expression of the osteogenic marker Runx2 and further contributes to EndMT. In addition, activation of NF-κB leads to down-regulation of integrin-linked kinase (ILK) expression (43). ILK maintains endothelial cell homeostasis and prevents their transformation to mesenchymal cells by inhibiting Smad2 phosphorylation in the normal state. However, under sustained inflammation, ILK deficiency predisposes VEC to transformation toward a mesenchymal phenotype and enhances the secretion of pro-calcitonin, accelerating the process of CAVD pathologic calcification (46). The inflammatory microenvironment further promotes CAVD progression by translating inflammatory signals into structural and functional damage through EndMT, a central mechanism.

EndMT: a central hub in the evolution of CAVD pathology

Overall, EndMT plays a central role in the onset, development, and progression of CAVD, connecting multiple pathologic signals such as shear stress, altered ECM composition, and inflammatory microenvironment. This cellular transformation process not only contributes to the loss of normal function of endothelial cells but also transforms them into osteoblast-like mesenchymal cells, which eventually form calcified lesions. Understanding the regulatory mechanism of EndMT in CAVD, especially its interaction with the TGF-β pathway, mechanical force induction and inflammatory signaling, will provide new ideas and potential intervention targets for targeted therapy of CAVD. These studies have not only enriched the understanding of the pathogenesis of CAVD but also laid the theoretical foundation for the development of precise, future therapeutic strategies for EndMT. However, it is worth noting that most current CAVD studies rely on in vitro EndMT experiments (e.g., TGF-β-treated aortic VEC), and these models may fail to fully mimic the complex pathological environment found in human disease. In vitro experiments lack the dynamic role of blood flow shear forces and interactions with other cell types, and thus may have limitations in modeling disease mechanisms in human CAVD. Future studies should explore more complex in vivo models to more accurately reflect the role of EndMT processes under real physiological conditions.

Potential therapeutic strategies and intervention targets for EndMT

EndMT plays an important role in the onset and progression of a variety of diseases, especially in pathological processes such as fibrosis, CAVD, and diabetic nephropathy. For the treatment of CAVD, several studies have proposed innovative strategies to target EndMT. For example, Arginine-glycine-aspartic acid (RGD-2) antagonists are able to effectively reverse EndMT by inhibiting the interaction of Alphavbeta3 integrin (avβ3) integrins with the TGF-β1 signaling pathway, showing potential especially in the early stage of CAVD (47). In addition, Losartan, an angiotensin II type 1 receptor antagonist, inhibits EndMT by blocking TGF-β-induced ERK phosphorylation, and has potential therapeutic efficacy especially in the advanced stages of CAVD (48). However, Losartan may cause side effects such as hypotension and hyperkalemia, a clinical limitation that requires attention.

During heart valve development, Snai1 promotes EndMT by regulating the expression of matrix metalloproteinase (MMP) 15, which has a critical role in valve pathology (49). Notch1 and vascular endothelial growth factor (VEGF) show opposing roles in heart VEC, and the complexity of their interactions provides new targets for CAVD therapy, but also increases the complexity of therapeutic strategies (50).

In diabetic nephropathy, the interaction between dipeptidyl peptidase (DPP)-4 and integrin β1 has been found to be an important mechanism for the development of EndMT, and the ability of DPP-4 inhibitors to ameliorate renal fibrosis and inhibit the progression of EndMT provides a new direction for the treatment of diabetic nephropathy (51). In addition, Kallistatin inhibits oxidative stress and slows down EndMT by regulating miR-21 and endothelial nitric oxide synthase (eNOS), and has shown some effects in the early stages of CAVD and the treatment of diabetic nephropathy (52). Despite the potential benefits of these clinical applications, they still face limitations such as side effects, and their long-term efficacy and safety need to be further investigated.

FOG-2 demonstrated its potential role in heart valve development by negatively regulating the EndMT process in cardiac development, however the feasibility of this mechanism for clinical interventions still needs to be thoroughly explored (53). Finally, the Smad3 inhibitor SIS3 was found to delay the early progression of diabetic nephropathy, providing new ideas for the treatment of EndMT in renal diseases (54).

Targeted therapy for EndMT: from theory to practice

EndMT has emerged as a key mechanism in the development of CAVD, and targeting this process holds great promise for providing more precise and effective treatment options for patients. However, translating EndMT-targeted therapies into clinical practice requires addressing several critical factors.

EndMT-targeted therapies are likely to be most effective in the early or pre-calcific stages of CAVD, in which valve remodeling and fibrosis are reversible before irreversible calcification occurs. Early-stage therapies could delay the need for surgery and improve long-term valve function.

The early detection of EndMT activation can be achieved through circulating biomarkers, such as soluble VE-cadherin, α-SMA, and microRNAs (e.g., miR-21). Additionally, advances in molecular imaging, such as PET scans or targeted ultrasound, may enable the noninvasive detection of EndMT and endothelial dysfunction in vivo.

While EndMT-targeted therapies are not meant to replace surgical options like surgical aortic valve replacement (SAVR) or TAVR, they could serve as adjunctive treatments. These therapies could delay disease progression, reduce the need for early surgery, or improve post-surgical outcomes by promoting valve healing and remodeling.

The development of targeted drugs against the core pathways regulating EndMT (e.g., TGF-β, Notch, Wnt) is expected to be a major focus of precision medicine for CAVD. Targeted drug delivery systems that can specifically modulate these pathways in aortic VEC will help minimize side effects and improve efficacy. Moreover, the combination of anti-inflammatory, anti-fibrotic, and anti-calcification therapies could offer a more comprehensive treatment approach, addressing multiple aspects of CAVD pathogenesis simultaneously.

In the future, the integration of EndMT-targeted therapy with existing surgical options, alongside the development of early diagnostic markers and new pharmacological agents, holds great potential to improve patient outcomes in CAVD. These advances could offer a more holistic and personalized approach to treating this progressive cardiovascular disease.

Discussion

Despite substantial progress in understanding the molecular mechanisms underlying CAVD, several knowledge gaps remain that hinder the development of effective, non-surgical treatments. One of the most significant challenges is the lack of human in vivo data. While animal models have been valuable in advancing our understanding of CAVD pathogenesis, they do not fully replicate the complexity of the disease in humans, particularly in terms of valve calcification and progression over time. As a result, the translation of promising therapeutic interventions, such as EndMT inhibitors, from preclinical models to clinical settings has been limited.

Moreover, the development of reliable biomarkers for early diagnosis and disease monitoring remains an unmet need in CAVD research. Early detection of EndMT activation, which plays a crucial role in CAVD progression, could potentially enable earlier intervention and better management of the disease. Biomarkers reflecting endothelial dysfunction, inflammation, and calcification could provide a non-invasive means to monitor disease activity and guide treatment decisions.

Future research should focus on developing animal models that more closely mimic human CAVD. Current models often do not capture the full spectrum of disease progression or reflect the long-term pathophysiological changes seen in human patients. In addition, clinical studies should aim to explore the translation of EndMT-targeted therapies from animal models to human trials. Given the promising preclinical data, understanding the safety, efficacy, and optimal application of EndMT inhibitors in human populations should be prioritized. Finally, identifying combination therapies that target multiple pathways involved in CAVD, including inflammation, fibrosis, and calcification, could provide a more holistic approach to treatment.

Conclusions

CAVD is a progressive disease with a pathologic process involving multiple mechanisms such as inflammation, lipid deposition, and osteoblastic differentiation. In recent years, EndMT has been suggested to play a key role in the development of CAVD, promoting fibrosis and osteogenesis of valve mesenchymal cells, and ultimately accelerating the calcification process. However, the specific regulatory mechanisms of EndMT in CAVD have not been fully elucidated, and the interactions between different signaling pathways and possible therapeutic intervention strategies still need to be further investigated. In the future, interventions targeting EndMT may provide new directions for the early diagnosis and treatment of CAVD.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-373/rc

Peer Review File: Available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-373/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-2025-373/coif). The authors have no conflicts of interest to declare.

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