Critical Role of Endothelial DRP1 in regulating metabolic, microvascular, and cardiac function

Project Summary/Abstract: Microvascular endothelial-dependent vasodilation in response to flow is achieved by the release of nitric oxide (NO) in healthy individuals but is mediated by hydrogen peroxide (H2O2) in individuals with coronary artery disease (CAD). Mitochondria are potent producers of reactive oxygen species (ROS), including H2O2, under physiological conditions, but overproduce ROS in cardiometabolic pathologies. Mitochondrial fission and fusion are known regulators of ATP and ROS production. Mitochondrial fission is primarily mediated by and dependent on the GTPase, dynamin-related protein 1 (DRP1). Hyper-fission, due to increased levels of or overactivation of DRP1, has been implicated in promoting cellular dysfunction in various cardiometabolic diseases. Our preliminary data indicate that blocking DRP1 may have vascular benefits for individuals with CAD and that the overexpression of endothelial DRP1 contributes to vascular dysfunction in both humans and rats. We therefore hypothesize that DRP1 and mitochondrial fission may be important regulators of endothelial vascular function. The overall goal of this proposal is to assess the role of endothelial DRP1 in vivo using a novel rodent model that drives the overexpression of a DRP1-GFP transgene specifically in the vascular endothelium. Aim 1 will investigate whether DRP1 mediates mitochondrial fragmentation and metabolic changes in the endothelium in both isolated endothelial cells and intact blood vessels. Aim 2 will determine if upregulated endothelial cell DRP1 leads to functional damage in the microvasculature and the heart.