This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 101/11/1130    most recent CIRCRESAHA.107.150110v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Clark, A. N. Articles by Tucker, A. L. Search for Related Content PubMed PubMed Citation Articles by Clark, A. N. Articles by Tucker, A. L. Related Collections Angiogenesis Related Article

(Circulation Research. 2007;101:1130.)
© 2007 American Heart Association, Inc.

Cellular Biology

A₁ Adenosine Receptor Activation Promotes Angiogenesis and Release of VEGF From Monocytes

Adam N. Clark, Rebecca Youkey, Xiaoping Liu, Liguo Jia, Rebecca Blatt, Yuan-Ji Day, Gail W. Sullivan, Joel Linden, Amy L. Tucker

From the Department of Internal Medicine, Cardiovascular Division (A.N.C., R.Y., X.L., L.J., R.B., G.W.S., J.L., A.L.T.), Molecular Physiology and Biological Physics (A.N.C., R.Y., A.L.T.), and Cardiovascular Research Center (A.N.C., R.Y., J.L., A.L.T.), University of Virginia Health System, Charlottesville; and the Transgenic & Molecular Immunogenetics Laboratory (Y.-J.D.), Department of Anesthesiology, Chang, Gung Memorial Hospital, Tauyuan Gueishan, Taiwan ROC.

Correspondence to Amy L. Tucker, Box 801394 MR5, University of Virginia Health System, Charlottesville, VA 22908. E-mail alt8t{at}virginia.edu

Adenosine is a proangiogenic purine nucleoside released from ischemic and hypoxic tissues. Of the 4 adenosine receptor (AR) subtypes (A₁, A_2A, A_2B, and A₃), the A₂ and A₃ have been previously linked to the modulation of angiogenesis. We used the chicken chorioallantoic membrane (CAM) model to determine whether A₁ AR activation affects angiogenesis. We cloned and pharmacologically characterized chicken AR subtypes to evaluate the selectivity of various agonists and antagonists. Application of the A₁ AR-selective agonist N⁶-cyclopentyladenosine (CPA; 100 nmol/L) to the CAM resulted in a 40% increase in blood vessel number (P<0.01), which was blocked by the A₁ AR-selective antagonist C⁸-(N-methylisopropyl)-amino-N⁶-(5'-endohydroxy)-endonorbornan-2-yl-9-methyladenine (WRC-0571; 1 µmol/L). Selective A_2A AR agonists did not stimulate angiogenesis in the CAM. In an ex vivo rat aortic ring model of angiogenesis that includes cocultured endothelial cells, fibroblasts, and smooth muscle cells, 50 nmol/L CPA did not directly stimulate capillary formation; however, medium from human mononuclear cells pretreated with CPA, but not vehicle, increased capillary formation by 48% (P<0.05). This effect was blocked by WRC-0571 (1.5 µmol/L) or anti-VEGF antibody (1 µg/mL). CPA (5 nmol/L) stimulated a 1.7-fold increase in VEGF release from the mononuclear cells. This is the first study to show that A₁ AR activation induces angiogenesis. Stimulation of A₂ ARs on endothelial cells results in proliferation and tube formation, and A₂ and A₃ ARs on inflammatory cells modulate release of angiogenic factors. We conclude that adenosine promotes a coordinated angiogenic response through its interactions with multiple receptors on multiple cell types.

Key Words: angiogenesis • receptor pharmacology • growth factors/cytokines

Related Article:

Adenosine Receptors and Angiogenesis

John A. Auchampach
Circ. Res. 2007 101: 1075-1077. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				S. Nakav, O. Naamani, C. Chaimovitz, G. Shaked, D. Czeiger, M. Zlotnik, and A. Douvdevani Regulation of adenosine system at the onset of peritonitis Nephrol. Dial. Transplant., October 26, 2009; (2009) gfp542v1. [Abstract] [Full Text] [PDF]

				S. Y. Cheranov, M. Karpurapu, D. Wang, B. Zhang, R. C. Venema, and G. N. Rao An essential role for SRC-activated STAT-3 in 14,15-EET-induced VEGF expression and angiogenesis Blood, June 15, 2008; 111(12): 5581 - 5591. [Abstract] [Full Text] [PDF]

				J. Shen and P. E. DiCorleto Adenosine Prompts the Heart to Recruit Endothelial Progenitors Circ. Res., February 15, 2008; 102(3): 280 - 282. [Full Text] [PDF]

				J. A. Auchampach Adenosine Receptors and Angiogenesis Circ. Res., November 26, 2007; 101(11): 1075 - 1077. [Full Text] [PDF]