Ischemic neoangiogenesis enhanced by β2-adrenergic receptor overexpression -: A novel role for the endothelial adrenergic system

beta(2)-Adrenergic receptors (beta(2)ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that beta(2)ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human beta(2)AR to the endothelium of the rat femoral artery and increased beta(2)AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that beta(2)AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-protein coupling defective mutant Ile164 beta(2)AR failed to provide ameliorations. Stimulation of endogenous and overexpressed beta(2)AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [H-3]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The beta(2)AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, beta(2)ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia.