Project Summary The prevalence of hypertension is growing steadily with the mortality reaching 30,221 from hypertensive and associated renal disease. While there is effective blood pressure reduction therapy, the underlying pathophysiology leading to the vascular remodeling and hypertensive end-organ damage remains poorly understood. Mitochondrial dysfunction has been implicated in various cardiovascular diseases. But the mechanism and role of mitochondrial quality control in hypertension is under-investigated. My preliminary data shows a role of enhanced mitochondrial fission via activation of dynamin-related GTPase, Drp1, in vascular smooth muscle cells (VSMCs) in hypertensive vascular remodeling. 100 nM Angiotensin II (AngII) treatment of rat aortic VSMCs induced transient mitochondrial fission (max at 2-4 h) and enhanced mitochondrial reactive oxygen species (ROS) production. Viral (ad-siDrp1) and pharmacological (mdivi1) inhibition of Drp1 attenuated AngII-induced mitochondrial fission as well as enhancement of mitochondrial ROS generation, total cell protein, cell volume and extracellular collagen content. In vivo, Mdivi1 suppressed vascular hypertrophy and perivascular fibrosis induced by 2 weeks AngII treatment (1000ng/kg/min) in aorta, heart and kidney (C57BL/6 mice). Mdivi1 also inhibited AngII-induced left ventricular hypertrophy and reduced KDEL and nitro-tyrosine staining in coronary and renal arteries suggesting attenuation of vascular ER stress and oxidative stress. We report that pharmacological inhibition of Drp1, prevents AngII-induced vascular remodeling. Based on these findings, I am proposing the following study to investigate our central hypothesis that mitochondrial fission mediates hypertensive vascular remodeling. I am trained by excellent co-PIs, Dr. Eguchi and Dr. Rizzo (Temple University), each with expertise in angiotensin signaling and vascular research. I will also be supported by leaders in angiotensin and mitochondrial research fields, respectively, Dr. Harrison (Vanderbilt University) and Dr. Sesaki (John Hopkins University). This proposal would both greatly advance my training and be in line with my career interests to explore cardiovascular pathophysiology as a physician-scientist and contribute to the search for novel treatments for hypertensive complications. To gain mechanistic insight into Drp1 activation by AngII and its effect in VSMC specific Drp1-/- mice in a hypertension model, I propose the following aims: 1. To examine the mechanism and consequences of AngII-induced mitochondrial fragmentation by targeting Drp1 in vascular smooth muscle cell (VSMCs) in vitro. 2. To test the roles of Drp1 in AngII-mediated vascular remodeling and mitochondrial dysfunction in vivo.