Ischemic neoangiogenesis enhanced by beta2-adrenergic receptor overexpression: a novel role for the endothelial adrenergic system.
Beta2-adrenergic receptors (beta2ARs) 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 beta2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human beta2AR to the endothelium of the rat femoral artery and increased beta2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that beta2AR 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 beta2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed beta2AR 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 beta2AR 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, beta2ARs 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.
Iaccarino
Guido
G
Dipartimento di Medicina Clinica e Scienze Cardiovascolari ed Immunologiche, Università Federico II, Naples, Italy. guiaccar@unina.it
Ciccarelli
Michele
M
Sorriento
Daniela
D
Galasso
Gennaro
G
Campanile
Alfonso
A
Santulli
Gaetano
G
Cipolletta
Ersilia
E
Cerullo
Vincenzo
V
Cimini
Vincenzo
V
Altobelli
Giovanna Giuseppina
GG
Piscione
Federico
F
Priante
Ornella
O
Pastore
Lucio
L
Chiariello
Massimo
M
Salvatore
Francesco
F
Koch
Walter J
WJ
Trimarco
Bruno
B
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D007511:Ischemia / Q000503:physiopathology*; D018919:Neovascularization, Physiologic; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D018343:Receptors, Adrenergic, beta-2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases