<p>Endothelial dysfunction is a hallmark of hypertension and a key contributor of hypertensive vascular damage. Mitochondrial oxidative stress serves as a central mediator that triggers endothelial dysfunction in hypertension. Activating Transcription Factor 4 (ATF4) is a key regulator of cellular stress responses; however, its role in maintaining endothelial mitochondrial redox homeostasis under hypertension remains to be fully elucidated. Through integrated bioinformatic profiling of public mouse aortic single-cell RNA sequencing (scRNA-seq) datasets, we identified a cell-type-specific upregulation of ATF4 within the endothelial cell cluster under both Angiotensin II (Ang II) and high-salt treatment, which was further validated in hypertensive murine aortas and Ang II-stimulated human umbilical vein endothelial cells (HUVECs). To investigate its functional role in vivo, endothelial-specific ATF4 overexpression was achieved via adeno-associated virus (AAV) delivery in Ang II-infused mice, which blunted blood pressure elevation and attenuated vascular damage. To dissect the underlying mechanisms in vitro, loss- and gain-of-function assays were performed in HUVECs using siRNA knockdown and adenovirus-mediated overexpression. Mechanistically, chromatin immunoprecipitation (ChIP-qPCR) and luciferase reporter assays demonstrated that ATF4 directly bound to the isocitrate dehydrogenase 2 (<i>IDH2</i>) promoter and transcriptionally activated its expression. Crucially, IDH2 knockdown recapitulated the detrimental effects of ATF4 silencing, confirming it as an important downstream mediator. Collectively, these findings demonstrate that the endothelial ATF4-IDH2 axis constitutes a novel protective pathway that safeguards mitochondrial redox homeostasis in hypertensive vascular damage. These findings suggest that ATF4-mediated transcriptional reprogramming of mitochondrial antioxidant defense may represent a promising therapeutic strategy for hypertensive vascular damage.</p>