Adenosine Receptor Activation Induces Vascular Endothelial Growth Factor in Human Retinal Endothelial Cells

Abstract

Adenosine, released in increased amounts by hypoxic tissues, is thought to be an angiogenic factor that links altered cellular metabolism caused by oxygen deprivation to compensatory angiogenesis. Adenosine interacts with 4 subtypes of G protein-coupled receptors, termed A(1), A(2A), A(2B), and A(3). We investigated whether adenosine causes proliferation of human retinal endothelial cells (HRECs) and synthesis of vascular endothelial growth factor (VEGF) and, if so, which adenosine receptor subtype mediates these effects. The nonselective adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), in a concentration-dependent manner, increased both VEGF mRNA and protein expression by HRECs, as well as proliferation. This proliferative effect of NECA was inhibited by the addition of anti-human VEGF antibody. NECA also increased insulin-like growth factor-I and basic fibroblast growth factor mRNA expression in a time-dependent manner and cAMP accumulation in these cells. In contrast, neither the A(1) agonist N(6)-cyclopentyladenosine nor the A(2A) agonist 2-p-(2-carboxyethyl) phenethylamino-NECA caused any of the above effects of NECA. The effects of NECA were not significantly attenuated by either the A(2A) antagonist SCH58261 or the A(1) antagonist 8-cyclopentyl-1, 3-dipropylxanthine. However, the nonselective adenosine receptor antagonist xanthine amine congener completely inhibited the effects of NECA. Addition of antisense oligonucleotide complementary to A(2B) adenosine receptor mRNA inhibited VEGF protein production by HRECs after NECA stimulation. Thus, the A(2B) adenosine receptor subtype appears to mediate the actions of adenosine to increase growth factor production, cAMP content, and cell proliferation of HRECs. Adenosine activates the A(2B) adenosine receptor in HRECs, which may lead to neovascularization by a mechanism involving increased angiogenic growth factor expression.

Adenosine A2A receptor regulates expression of vascular endothelial growth factor in feto-placental endothelium from normal and late-onset pre-eclamptic pregnancies

“…However, it has been described that adenosine A 2A (and A 2B ) receptors may increase endothelial proliferation/migration and in vitro angiogenesis capacity, as well as induce vasodilatation, increase the synthesis of proangiogenic factors (i.e., VEGF), or decrease expression of antiangiogenic factors such as sFLT-1 [see details in 1]. In particular, other [2,4,6] and we [14,36] have previously showed that stimulation of A 2A receptor increased the expression of VEGF in endothelial cells, as confirmed in the current work.…”

“…Adenosine is a nucleoside, which activates a family of Gcoupled protein receptors, named adenosine receptor (AR), type 1 (A 1 ), 2A (A 2A ), 2B (A 2B ), and 3 (A 3 ), and can control expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) [1][2][3][4][5][6]. However, depending on the tissue or cell approach, A 2A and A 2B may play a dominant role in regulating pro-angiogenic processes [2,4,7,8].…”

The A2b adenosine receptor protects against vascular injury

“…In general, the A2-type receptors have been described as sensors of tissue damage during an immune response (2), and A2aARs have been described as having a nonredundant role in the attenuation of inflammation and tissue damage in vivo (3). Indirect evidence suggests that the adenylyl cyclase stimulatory A2b adenosine receptors (A2bARs) also affect vascular function (4)(5)(6). For instance, adenosine inhibits the proliferation of murine VSMC via activation of the A2bAR (4).…”

“…For instance, adenosine inhibits the proliferation of murine VSMC via activation of the A2bAR (4). On the other hand, A2bAR activation induces growth of human vascular endothelial cells and stimulates MAP kinase activity in other cell types (5,6). Additional studies suggest that adenosine induces apoptosis of human arterial smooth muscle cells, which is mediated via the A2bAR in a cAMP-dependent pathway (7).…”

Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model

“…In contrast, when adenosine activates the A 2A receptors, cAMP level increases, which causes airway relaxation (29). Adenosine A 2B receptors have long been known to be coupled to G s protein, which mediates the activation of adenylyl cyclase (12,33). Recent studies indicate that A 2B receptors are also coupled to G q and result in Ca 2ϩ mobilization and mitogen-activated protein kinase activation (20,21).…”