Published online before print October 20, 2005, doi: 10.1161/01.RES.0000191541.06788.bb
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Submitted on December 13, 2004
Revised on June 16, 2005
Accepted on October 10, 2005
Ischemic Neoangiogenesis Enhanced by 
2-Adrenergic Receptor Overexpression. A Novel Role for the Endothelial Adrenergic System
Guido Iaccarino *;
From the Dipartimento di Medicina Clinica (G.I., M.C., D.S., G.G., A.C., G.S., E.C., F.P., O.P., M.C., B.T.), Scienze Cardiovascolari ed Immunologiche, Università Federico II, Napoli, Italy; Dipartimento di Biochimica e Biotecnologie Mediche (V.C., L.P., F.S.), Università Federico II, Napoli, Italy; CEINGE-Biotecnologie Avanzate (V.C., L.P., F.S.), Napoli, Italy; Dipartimento di Scienze Biomorfologiche e Funzionali (V.C., G.G.A.), Università Federico II, Napoli, Italy; Center for Translational Medicine (W.J.K.), Thomas Jefferson University, Philadelphia, Pa; and IRCCS Neuromed (B.T.), Pozzilli, Italy.
* To whom correspondence should be addressed. E-mail: guiaccar{at}unina.it.
2-Adrenergic receptors (2ARs) 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 2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human 2AR to the endothelium of the rat femoral artery and increased 2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that 2AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in hypertensive SHR rats, whereas gene delivery of the G-protein-coupling defective mutant Ile164 2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed 2AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [3H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The 2AR 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, 2ARs 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.
Key words: angiogenesis • rats • polymorphism • hypertension • in vivo digital angiography
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