Targeting endothelial cytoskeletal remodeling to restore angiogenesis in ischemic heart disease

Ischemic heart disease (IHD) remains a leading cause of morbidity and mortality worldwide. Effective restoration of myocardial perfusion relies on angiogenesis, a process frequently impaired in patients due to endothelial dysfunction. Endothelial cells orchestrate angiogenesis through dynamic cytoskeletal remodeling, which regulates migration, polarity, proliferation, and lumen formation. This review summarizes the molecular mechanisms underlying endothelial cytoskeletal remodeling and how their dysregulation contributes to angiogenesis failure in IHD. We focus on alterations in actin filaments, microtubules, and intermediate filaments, and upstream signaling pathways involved in mechanotransduction, Rho GTPase signaling, and cellular metabolism. Importantly, we highlight therapeutically actionable strategies aimed at restoring endothelial function, including pharmacological modulation of cytoskeletal regulators, epigenetic interventions, and biomaterial-based approaches. A major limitation of the current literature is that most mechanistic insights are derived from non-cardiac vascular beds (e.g., retina, brain, lung); where applicable, we explicitly distinguish cardiac-specific evidence from extrapolated findings. By integrating mechanistic insights with translational perspectives, this review provides a framework for developing targeted pro-angiogenic therapies in IHD, while emphasizing the urgent need for direct validation in human coronary endothelium.