A ₁ Adenosine Receptor Activation Promotes Angiogenesis and Release of VEGF From Monocytes

Abstract

Abstract-Adenosine is a proangiogenic purine nucleoside released from ischemic and hypoxic tissues. Of the 4 adenosine receptor (AR) subtypes (A 1 , A 2A , A 2B , and A 3 ), the A 2 and A 3 have been previously linked to the modulation of angiogenesis. We used the chicken chorioallantoic membrane (CAM) model to determine whether A 1 AR activation affects angiogenesis. We cloned and pharmacologically characterized chicken AR subtypes to evaluate the selectivity of various agonists and antagonists. Application of the A 1 AR-selective agonist N 6 -cyclopentyladenosine (CPA; 100 nmol/L) to the CAM resulted in a 40% increase in blood vessel number (PϽ0.01), which was blocked by the A 1 AR-selective antagonist C 8 -(N-methylisopropyl)-amino-N 6 -(5Ј-endohydroxy)-endonorbornan-2-yl-9-methyladenine (WRC-0571; 1 mol/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% (PϽ0.05). This effect was blocked by WRC-0571 (1.5 mol/L) or anti-VEGF antibody (1 g/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 A 1 AR activation induces angiogenesis. Stimulation of A 2 ARs on endothelial cells results in proliferation and tube formation, and A 2 and A 3 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. (Circ Res.

Extracellular adenosine triphosphate and adenosine in cancer

“…Adenosine receptor signaling A1 and A3 adenosine receptors inhibit adenylyl cyclase and protein kinase A activity, thus decreasing intracellular cAMP levels, with studies revealing an important function in cardioprotection (Liang and Jacobson, 1998;Reichelt et al, 2005;Hochhauser et al, 2007), angiogenesis (Clark et al, 2007) and protection against septic shock (Gallos et al, 2005). A1 and A3 adenosine receptors have also been linked to phosphatidylinositol 3-kinase, mitogen-activated protein kinase and protein kinase C pathways (Hasko and Cronstein, 2004;Gessi et al, 2008).…”

Retinopathy of prematurity: understanding ischemic retinal vasculopathies at an extreme of life

“…Similarly, selective antagonists of the A 2B adenosine receptor profoundly reduce preretinal neovascularization (on the retinal-vitreal interface) (Figure 1) (129). It is noteworthy that both succinate and adenosine derive their angiogenic potential from cells other than the endothelium; monocytes express adenosine receptors (133), while neurons (retinal ganglion cells) express both adenosine and succinate receptors (83,134). Deficiency in monocytes or retinal ganglion cells (either by destruction or genetic ablation) interferes profoundly with retinal vascular development in mice (83,135).…”

P2X1 receptor-mediated inhibition of the proliferation of human coronary smooth muscle cells involving the transcription factor NR4A1

“…The cells also express a variety of G-protein coupled receptors for extracellular nucleotides and its breakdown product adenosine. These G-protein coupled receptors contribute to both the control of the vascular tonus by adenosine and nucleotides [5][6][7][8][9] and the control of the proliferation of the vascular smooth muscle [5,[9][10][11][12][13][14][15][16][17].…”