Endothelial-to-mesenchymal transition in ischemic diseases: Molecular mechanisms, pathophysiological roles, and emerging therapeutic strategies.

Ischemic diseases, characterized by insufficient blood perfusion and vascular dysfunction, are a major cause of morbidity and mortality worldwide, including myocardial infarction (MI), ischemic stroke (IS), peripheral artery disease (PAD), and ischemic retinopathy. Endothelial-to-mesenchymal transition (EndMT) plays important roles in both physiological and pathophysiological processes. Under physiological conditions, EndMT is a tightly regulated developmental process required for embryonic cardiovascular formation. However, under pathological conditions such as ischemia, EndMT can be aberrantly activated by hypoxia, inflammatory signaling, and oxidative stress. Accumulating evidence indicates that EndMT plays dual roles in ischemic diseases. Partial EndMT may contribute to adaptive vascular remodeling and angiogenesis during the early phase of tissue injury, whereas persistent activation promotes endothelial dysfunction, extracellular matrix deposition, fibrosis, and chronic inflammation, thereby exacerbating disease progression. In this review, we summarize the current understanding of EndMT in ischemic diseases, focusing on the major regulatory signaling pathways, including TGF-β/Smad, Wnt/β-catenin, and Notch signaling, as well as epigenetic mechanisms such as histone modifications, DNA methylation, and non-coding RNAs. We further discuss emerging therapeutic strategies targeting EndMT, encompassing endogenous hormones, traditional Chinese medicine formulations, natural compounds, small molecule compounds, and RNA-based therapeutics. The clinical translation of EndMT is hindered by the lack of standardized diagnostic criteria and the limitations of existing experimental models. A deeper understanding of the EndMT regulatory network may provide new insights into vascular remodeling and facilitate the development of novel therapeutic strategies.