Targeting Mitochondrial Dynamics in VEGFR-TKI Hypertension and Cardiotoxicity

Cardiovascular toxicity has emerged as one of the most pressing clinical challenges in the era of precision oncology.Among the expanding arsenal of targeted anticancer agents, vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) occupy a prominent position, offering meaningful survival advantages across multiple tumor types.However, the cardiovascular price of these therapeutic benefits is increasingly difficult to ignore.Hypertension, the most frequently encountered cardiovascular adverse event associated with VEGFR-TKI therapy, affects a substantial proportion of treated patients and can precipitate dose reductions, treatment discontinuation, or serious cardiovascular events. 1 The challenge facing oncologists and cardiologists alike is therefore not merely one of managing blood pressure (BP), but of understanding the biological mechanisms by which these agents perturb vascular homeostasis, and identifying intervention strategies that can mitigate cardiovascular toxicity without compromising antitumor efficacy.The endothelium occupies a central position in this pathophysiology.Under physiological conditions, the endothelium serves as a dynamic, metabolically active interface between the circulating blood and the underlying vascular smooth muscle, orchestrating vasodilation primarily through the production of nitric oxide (NO) via the PI3K-AKT-eNOS signaling cascade. 2 The binding of VEGF-A to VEGFR-2 constitutes a critical upstream stimulus for this pathway, and its pharmacological inhibition by VEGFR-TKIs predictably impairs NO bioavailability while simultaneously activating the vasoconstrictor endothelin-1 (ET-1) pathway.Mitochondria are dynamic organelles regulated by fusion proteins, including mitofusins 1 and 2 (MFN1/2) and optic atrophy protein 1 (OPA1), and fission proteins, including dynamin-related protein 1 (Drp1), fission protein 1 (Fis1), and mitochondrial fission factor (MFF).In endothelial cells, excessive Drp1-mediated mitochondrial fission promotes mitochondrial reactive oxygen species (mitoROS) production, impaired eNOS phosphorylation, reduced NO bioavailability, and apoptosis, thereby contributing to endothelial dysfunction.Drp1-mediated pathological fission has been implicated in essential hypertension, 3 and pharmacological Drp1 inhibition with mitochondrial division