Stephen F. Vatner
Cardiovascular Research Institute, Rutgers-New Jersey Medical School, NJ, USA
Title: Overexpression of Cardiomyocyte Alpha1A-Adrenergic Receptors Protects the Ischemic Heart by Inducing Angiogenesis Through Heterocellular Signaling
Biography
Biography: Stephen F. Vatner
Abstract
Four to six weeks after permanent coronary artery occlusion (CAO), transgenic (TG) rats with cardiomyocyte-specific α1A-AR overexpression had better preserved left ventricular ejection fraction and wall stress with less myocardial fibrosis and hypertrophy than their non-transgenic littermates (NTLs). We reasoned that with total permanent CAO, in a model devoid of preformed collateral vessels, that the salutary response to CAO must have involved angiogenesis. Indeed, coronary blood flow, measured with microspheres, increased in the infarct zone in TG compared to NTLs (1.4±0.2 vs. 0.5±0.08ml/min/g) (p<0.05), which is consistent with angiogenesis, as reflected by a 20% increase in capillary density in the zone adjacent to the infarct. The question arose, how does TG overexpression of a gene in cardiomyocytes affect the coronary blood vessels to induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A (VEGF-A) mRNA and protein were increased in isolated TG cardiomyocytes, and also by NTL cardiomyocytes treated with an α1A-agonist, resulting in angiogenesis. Conditioned medium from cultured TG cardiomyocytes enhanced human umbilical vein endothelial cell (HUVEC) tubule formation, which was blocked by an anti-VEGF-A antibody. Moreover, improved cardiac function, blood flow and increased capillary density after chronic CAO in TG rats were also blocked by a VEGF-A inhibitor. Thus, cardiomyocyte-specific overexpression of the α1A-AR resulted in enhanced cardiomyocyte VEGF-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signalling, protecting against heart failure following chronic CAO.