Mitochondrial Fission in Vascular Cells Mediates Hypertensive Vascular Remodeling and Inflammation

Worldwide, high blood pressure affects nearly 1/3 of adults and is the most common cause of cardiovascular disease-related deaths. While there is effective blood pressure reduction therapy, the underlying pathophysiology leading to the hypertensive end-organ damage including the mechanism of vascular remodeling remains poorly understood. Mitochondrial dysfunction has been implicated in various cardiovascular diseases. Currently, there is little understanding on mechanism and role of mitochondrial quality control in hypertension. Our data shows that activation of mitochondrial fission via a dynamin-related GTPase, Drp1, is involved in hypertensive vascular remodeling. In vivo, 8-week old male C57BL/6 mice were infused with AngII (1000ng/kg/min) for 2 weeks with or without treatment with a Drp1 inhibitor, mdivi1, (25 mg/kg ip every other day). Mdivi1 suppressed vascular hypertrophy and perivascular fibrosis induced by AngII in aorta (thickness Mean±SEM: 0.291±.012 AngII only vs. 0.275±.006 AngII + mdivi1; p=0.07) and heart (LV wall thickness Mean±SEM: 0.423±.034 AngII only vs. 0.219±.017 AngII + mdivi1; p<0.01). Mdivi1 also inhibited AngII-induced left ventricular hypertrophy but not the elevated blood pressure measured continuously by telemetry. Reduced KDEL and nitro-tyrosine staining in coronary and renal arteries suggests attenuation of vascular ER stress and oxidative stress, respectively, in mdivi1 treated mice. To assess the role of acute signaling in this model C57BL/6 mice went through the same protocol for only 3 days. Several inflammatory targets (VCAM1, MMP2, HMGB1) were upregulated in aortas of AngII stimulated mice and attenuated with mdivi1 treatment. In addition, inhibition of mitochondrial fission (mdivi1) attenuated AngII-induced leukocyte adhesion at mesenteric micro-circulation assessed by intravital microscopy. In vitro , Ang-II induced inflammatory response in rat aortic endothelial cells (ECs) with THP-1 adhesion assay was attenuated by mdivi1 and an ER stress inhibitor (4-PBA). In conclusion, these data suggest that inhibition of mitochondrial fission prevents AngII-induced cardiovascular remodeling and inflammation through attenuating VSMC as well as EC signaling events.