Overexpression of Cardiomyocyte α 1A -Adrenergic Receptors Attenuates Postinfarct Remodeling by Inducing Angiogenesis Through Heterocellular Signaling

Abstract

Objective— Stimulation of cardiac α 1A -adrenergic receptors (α 1A -AR) has been proposed for treatment of heart failure, since it increases myocardial contractility. We investigated a different mechanism, induction of angiogenesis. Approach and Results— Four to 6 weeks after permanent coronary artery occlusion, transgenic rats with cardiomyocyte-specific α 1A -adrenergic receptor overexpression had less remodeling than their nontransgenic littermates, with less fibrosis, hypertrophy and lung weight, and preserved left ventricular ejection fraction and wall stress (all P <0.05). Coronary blood flow, measured with microspheres, increased in the infarct zone in transgenic rats compared with nontransgenic littermates (1.4±0.2 versus 0.5±0.08 mL min −1 g −1 ; 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 transgenic overexpression of a gene in cardiomyocytes induce angiogenesis? We identified a paracrine mechanism, whereby vascular endothelial growth factor-A mRNA and protein were increased in isolated transgenic cardiomyocytes and also by nontransgenic littermate cardiomyocytes treated with an α 1A -agonist, resulting in angiogenesis. Conditioned medium from cultured cardiomyocytes treated with an α 1A agonist enhanced human umbilical vein endothelial cell tubule formation, which was blocked by an anti–vascular endothelial growth factor-A antibody. Moreover, improved cardiac function, blood flow, and increased capillary density after chronic coronary artery occlusion in transgenic rats were blocked by either a mitogen ERK kinase (MEK) or a vascular endothelial growth factor-A inhibitor. Conclusion— Cardiomyocyte-specific overexpression of the α 1A -adrenergic receptors resulted in enhanced MEK-dependent cardiomyocyte vascular endothelial growth factor-A expression, which stimulates angiogenesis via a paracrine mechanism involving heterocellular cardiomyocyte/endothelial cell signaling, protecting against remodeling and heart failure after chronic coronary artery occlusion.