Endothelial mitochondrial homeostasis in the development and progression of atherosclerosis

Vascular endothelial cells (ECs) play a critical role in vascular functional homeostasis, and endothelial dysfunction activates signaling pathways that drive the development and progression of atherosclerosis. Mitochondria in ECs play an essential signaling role in regulating redox balance, calcium signaling, metabolic signaling, and inflammatory responses. Disruption of mitochondrial functional homeostasis by atherogenic stimuli leads to excessive mitochondrial reactive oxygen species production, altered mitochondrial dynamics, defective mitophagy, and mitochondrial DNA damage. These mitochondrial defects in ECs reduce nitric oxide bioavailability through eNOS uncoupling, destabilize endothelial junctional complexes, and promote endothelial activation. Additionally, damaged mitochondria release mitochondrial danger-associated molecular patterns contributing to the activation of inflammation and redox-sensitive signaling pathways in ECs. In this review, we delineated the mechanistic links between endothelial mitochondrial dysfunction and the pathological features of atherosclerosis. We highlight the contribution of mitochondrial signaling to the regulation of oxidative stress, innate immune activation, and endothelial barrier disruption. We also discussed emerging therapeutic strategies targeting mitochondria-associated signaling pathways, including modulation of mitochondrial dynamics, mitophagy, redox signaling, and mitochondria-targeted drug delivery. Together, we provide insights into the role of endothelial mitochondria in atherosclerotic disease progression and compelling targets for mechanism-based therapeutic intervention.