Aidan Atkins

Background: Endothelial‑to‑mesenchymal transition (EndMT) is a phenotypic switch in which endothelial cells lose markers such as CD31 and VE‑cadherin and acquire mesenchymal features, including α‑smooth muscle actin, vimentin, and N‑cadherin.¹ Although EndMT is required for normal valvulogenesis, its reactivation in adult tissues has been linked to myocardial fibrosis, valvular thickening, and progression of calcific aortic valve disease.² Recent work suggests that inflammatory cytokines, loss of protective adhesion molecules, and pathologic mechanical cues converge on EndMT pathways in cardiac and valvular endothelium, but these pathways are not yet routinely considered as therapeutic targets.³ This review examines how EndMT contributes to cardiac valvular fibrosis and explores whether modulating EndMT could offer a preventative disease strategy beyond current hemodynamic and surgical interventions.

Methods: A literature search was performed in PubMed for articles on EndMT and cardiac or valvular fibrosis published between 2016 and 2026. Primary mechanistic studies in animal, cell culture, and human valve tissue were included, and key reviews in EndMT and cardiovascular mechanobiology were screened for additional references on valvular pathology and therapeutic targeting.

Results: EndMT contributes to fibrosis in several experimental models directly relevant to cardiac and valvular remodeling, including post‑myocardial infarction fibrosis, angiotensin II-induced cardiac fibrosis, and calcific aortic valve disease.^4–6 After myocardial infarction, inflammatory upregulation of TNF‑α and endothelin-1 was associated with increased EndMT markers. In vitro experiments demonstrated that TNF‑α promoted EndMT through endothelin-1-dependent SMAD2 phosphorylation, which was later inhibited through endothelin‑1 downregulation.⁴ Loss of the adhesion molecule CD146 led to reduced endothelial marker expression, increased mesenchymal markers, and activation of the Wnt/β‑catenin pathway, whereas CD146 upregulation preserved endothelial characteristics and limited transition.⁶ In a disease‑inspired aortic valve model, elevated hyaluronic acid and excessive cyclic stretch induced EndMT, while physiologic stretch acted as a protective mechanism. Human calcific valve specimens showed consistent EndMT features that correlated with disease severity.⁵

Conclusions: EndMT appears to be a central link between endothelial injury, abnormal mechanical and biochemical cues, and the expansion of profibrotic cell populations in cardiac valves. Collectively, current data suggest that targeted modulation of EndMT, through inhibition of TNF‑α/endothelin‑1, preservation of protective molecules such as CD146, blockade of Wnt/β‑catenin and TGF‑β signaling, or optimization of valvular mechanics, may provide a preventative approach to cardiac valvular fibrosis. Future work should quantify the contribution of EndMT to human valvular fibroblast populations, develop pathway‑specific biomarkers to identify patients with EndMT‑dominant disease, and test EndMT‑directed therapies in translational models as a step toward clinical trials.

Works Cited

1. Cheng W, Li X, Liu D, Cui C, Wang X. Endothelial-to-Mesenchymal Transition: Role in Cardiac Fibrosis. J Cardiovasc Pharmacol Ther. 2021;26(1):3-11. doi:10.1177/1074248420952233
2. Hall IF, Aikawa E, Sluimer J, Baker AH, Kovacic JC. Endothelial to mesenchymal transition in cardiovascular diseases: molecular insights and clinical perspectives. Eur Heart J. 2026;47(10):1144-1158. doi:10.1093/eurheartj/ehaf670
3. Kovacic JC, Dimmeler S, Harvey RP, et al. Endothelial to Mesenchymal Transition in Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(2):190-209. doi:https://doi.org/10.1016/j.jacc.2018.09.089
4. Hu H, Huang J, Zhang S, Zhang B, Li W, Sun K. Tumor necrosis factor-α stimulation endothelial-to-mesenchymal transition during cardiac fibrosis via endothelin-1 signaling. J Biochem Mol Toxicol. 2023;37(9):e23411. doi:10.1002/jbt.23411
5. Mirzaalikhan Y, Lai A, Khanmohammadi M, et al. A disease-inspired in vitro model of aortic valve stenosis to investigate the drivers of endothelial-mesenchymal transition. Lab Chip. 2025;25(18):4635-4649. doi:10.1039/d5lc00484e
6. Zhang ZY, Zhai C, Yang XY, Li HB, Wu LL, Li L. Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/β-catenin pathway. PloS One. 2022;17(8):e0273542. doi:10.1371/journal.pone.0273542