Abstract P235: Endothelium-Specific Prokineticin Receptor 1 Inactivation in Mice Leads to Endothelial Dysfunction and Metabolic Syndrome
Reciprocal relationships between endothelial dysfunction and insulin resistance result in a vicious cycle, linking between cardiovascular and metabolic disorders. Here we provide the first evidence that endothelial specific loss of prokineticin receptor-1 (PKR1) in mice leads to endothelial dysfunction and low capillary formation, ultimately contributing cardiovascular, kidney disorders and development of insulin resistance. Endothelial cells derived from these mutant hearts displayed an impaired proliferation rate and vessel-like formation. Low capillary formation in mutant heart, kidney, pancreas and adipose tissues was evident. The mutant aortas displayed increased collagen deposition, fenestrated endothelium with junctional defects, and impaired relaxation due to nitric oxide synthesize-deficits without altering blood pressure. Mutant hearts have thin ventricular wall due to an increase in apoptotic cardiomyocytes. Mutant kidneys have abnormal glomerulus structure with an increase in apoptotic cell numbers and phosphate excretion. Mutant mice exhibited low fasting blood glucose and high serum insulin levels. They cleared the blood glucose at a considerably slower rate than control mice accompanied with impaired insulin tolerance. The insulin resistance induces compensatory β cell hypertrophy but not expansion due to impaired survival signaling. Induction of cell death and fibrosis is induced by hypoxia in mutant adipocytes leads to increase in HIF1a and collagen expression. Moreover, an increase in serum FFA and inhibition of insulin-signaling pathway in adipocytes may represent an early event in systemic insulin resistance. This mutation provides a genetic model for metabolic syndrome and should facilitate studies of both the pathogenesis and therapy of cardiovascular, renal and metabolic disorders in humans.
- © 2011 by American Heart Association, Inc.