β ₂ -Adrenergic receptors (β 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 β ₂ ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human β ₂ AR to the endothelium of the rat femoral artery and increased β ₂ AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that β 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 β ₂ AR failed to provide ameliorations. Stimulation of endogenous and overexpressed β ₂ AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [ ³ H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The β 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, β 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.