Mitochondrial dysfunction in endothelial senescence: implications for vascular remodeling and therapeutic strategies.

Abstract

Vascular remodeling (VR) is a structural and functional adaptation of the vessel wall to hemodynamic, metabolic, and inflammatory stress. When persistent and dysregulated, it contributes to the progression of atherosclerosis, hypertension, pulmonary arterial hypertension, and brain microvascular disease. Endothelial senescence is increasingly recognized as a key component of this maladaptive transition, characterized by impaired endothelial homeostasis, reduced nitric oxide bioavailability, and a senescence-associated secretory phenotype (SASP) that can reshape vascular cell-cell communication and extracellular matrix remodeling. Recent evidence further suggests that mitochondrial dysfunction is closely linked to endothelial senescence through multiple mechanisms, including mtROS accumulation, mitochondrial DNA (mtDNA) damage and leakage, disturbed mitochondrial dynamics, and impaired mitophagy flux. In this review, we integrate these findings into a vascular-bed- and disease-stage-stratified conceptual framework, termed the mitochondrial dysfunction-endothelial senescence-vascular remodeling (MD-ES-VR) axis. Within this framework, mechanisms and interventions are interpreted according to evidence strength, causal level, vascular context, and remodeling stage. Current evidence most consistently supports roles for mitochondrial dysfunction in amplifying endothelial injury, inflammatory senescence-like signaling, and remodeling progression, whereas definitive proof for reversal of established structural lesions remains limited. We therefore propose that future studies should combine endothelial-specific and time-resolved designs with quantitative mitochondrial and senescence readouts and robust structural endpoints to better define causality, therapeutic windows, and translational potential.