Endothelial microvascular dysfunction is a critical and independent risk factor for coronary artery disease (CAD)

Endothelial microvascular dysfunction is a critical and independent risk factor for coronary artery disease (CAD). Mitochondrial dynamics play a crucial role in energy homeostasis, adapt based on cellular energetic needs, and contribute to proper endothelial function. Mitochondrial fission is mediated by DRP1 and has been directly implicated in ROS overproduction, calcium homeostasis dysregulation, and cellular metabolism dysfunction. Furthermore, mitochondrial fission is linked to cardiometabolic disease states including pulmonary arterial hypertension, obesity, sedentary lifestyle, and type 2 diabetes which are all notable risk factors for CAD. We therefore aim to assess the role of DRP1 in mediating microvascular endothelial dysfunction and to determine the contributions of endothelial-driven multi-organ dysfunction. To test this, we have generated a new transgenic rodent model by crossing a VE-Cadherin Cre and flox-stop DRP1-GFP to create a rat model that overexpresses DRP1 in the endothelium (EC-DRP1). Vascular flow-induced dilation studies show that EC-DRP1 rats have impaired vascular function when compared to littermate controls (max dilation at 41.2% to 80.3%, p<0.05). Cardiac function, measured by echocardiography, was decreased in EC-DRP animals when compared to littermate controls [left ventricular ejection fraction = (76.3% to 83.7%, p<0.05), cardiac output = (0.81 to 0.68 L/min, p<0.05)]. Furthermore, impaired autophagy was observed in kidney tissue from EC-DRP animals compared to controls [relative protein expression measured by WB of LC3B II:I = (1.22 to 0.00) and p62 = (1.28 to 0.82)], although no significant differences were seen in KIM-1 expression (1.14 to 1.19). No blood pressure differences by radiotelemetry were observed. Understanding the critical links between mitochondrial fission, endothelial dysfunction, and cardiometabolic disease may provide novel avenues of therapy.