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

Guido Iaccarino, Michele Ciccarelli, Daniela Sorriento, Gennaro Galasso, Alfonso Campanile, Gaetano Santulli, Ersilia Cipolletta, Vincenzo Cerullo, Vincenzo Cimini, Giovanna Giuseppina Altobelli, Federico Piscione, Ornella Priante, Lucio Pastore, Massimo Chiariello, Francesco Salvatore, Walter J. Koch, Bruno Trimarco

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

β2-Adrenergic receptors (β2ARs) 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 β2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human β2AR to the endothelium of the rat femoral artery and increased β2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that β2AR 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 β2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed β2AR 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 β2AR 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, β2ARs 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.

Original languageEnglish (US)
Pages (from-to)1182-1189
Number of pages8
JournalCirculation research
Volume97
Issue number11
DOIs
StatePublished - Nov 1 2005
Externally publishedYes

Keywords

  • Angiogenesis
  • Hypertension
  • In vivo digital angiography
  • Polymorphism
  • Rats

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Iaccarino, G., Ciccarelli, M., Sorriento, D., Galasso, G., Campanile, A., Santulli, G., Cipolletta, E., Cerullo, V., Cimini, V., Altobelli, G. G., Piscione, F., Priante, O., Pastore, L., Chiariello, M., Salvatore, F., Koch, W. J., & Trimarco, B. (2005). Ischemic neoangiogenesis enhanced by β2-adrenergic receptor overexpression: A novel role for the endothelial adrenergic system. Circulation research, 97(11), 1182-1189. https://doi.org/10.1161/01.RES.0000191541.06788.bb