Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1
Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1
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DOI：
10.1124/mol.104.007807
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发表时间：
2005-05-01
影响因子：
3.6
通讯作者：
Cronstein, BN
中科院分区：
文献类型：
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作者：
Desai, A;Victor-Vega, C;Cronstein, BN
外用腺苷A(2A)受体激动剂通过增加微血管形成等作用促进伤口愈合。人脐静脉内皮细胞代表性展示分析结果表明，A(2A)受体可调节抗血管生成基质蛋白血栓反应素1(TSP1)的表达。因此，我们确定了A(2A)受体是否通过调节TSP1的分泌来刺激血管生成。用选择性A(2A)受体激动剂2-p-[2-羧乙基]phenethyl-amino-5‘-N-ethylcarboxamido-adenosine(CGS21680)或2-[2-(4-氯苯基)乙氧基]腺苷(MRE0094)单独作用于人微血管内皮细胞。A2A型激动剂CGS21680或MRE0094作用后，TSP1蛋白分泌呈剂量依赖性下调(EC50分别为6.65 nM和0.23 mM)。选择性A(2A)受体拮抗剂4-{2-[7-氨基-2-(2-呋喃)[1，2，4]三唑-[2，3a][1，3，5]三氮-5-氨基]乙基}苯酚(ZM241385)，但不能阻断A1和A(2B)受体拮抗剂二苯基环戊基黄嘌呤、依普洛林和N-(4-acetylphenyl)-2-[4-(2，3，6，7-tetrahydro2，6-dioxo-1，3-dipropyl-1H-purin-8-yl)phenoxy]acetamide(MRS1706)，可完全阻断A(2A)受体激动剂的作用。腺苷A2 A受体激动剂呈剂量依赖性地促进HMVEC的血管形成(EC50=6.65 mU M)，A(2A)拮抗剂可逆转这一作用。此外，在TSP1和TSP1受体CD36的抗体存在的情况下，腺苷A(2A)受体激动剂刺激血管形成的NO增加。这些结果表明，腺苷A(2A)受体激活的血管生成作用至少部分是由抑制TSP1分泌引起的。
Topical adenosine A(2A) receptor agonists promote wound healing by, among other effects, increasing microvessel formation. Results of representational display analysis of human umbilical vein endothelial cells suggested that A(2A) receptor occupancy modulates expression of the antiangiogenic matrix protein thrombospondin 1 (TSP1). We therefore determined whether A(2A) receptor occupation stimulates angiogenesis by modulating TSP1 secretion. Human microvascular endothelial cells (HMVEC) were treated with medium alone, 2-p-[2- carboxyethyl] phenethyl-amino-5'-N-ethylcarboxamido-adenosine (CGS21680), or 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094), selective A(2A) receptor agonists. TSP1 protein secretion was down- regulated after treatment with the A 2A agonists CGS21680 or MRE0094 in a dose-dependent manner (EC50 = 6.65 nM and 0.23 mu M, respectively). The selective A(2A) receptor antagonist 4-{2-[7-amino-2-(2-furyl)[1,2,4] triazolo-[2,3a][ 1,3,5] triazin-5-ylamino]ethyl}phenol (ZM241385) but not the A1 and A(2B) receptor antagonists diphenylcyclopentylxanthine, enprofylline, and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro2,6- dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS1706) completely abrogated the A(2A) receptor agonistmediated effect on TSP1. Vascular tube formation by HMVEC was increased by adenosine A 2A receptor agonists in a dosedependent fashion (EC50 = 6.65 mu M for both), and this effect was reversed by the A(2A) antagonist. Moreover, in the presence of antibodies to TSP1 and CD36, the receptor for TSP1, the adenosine A(2A) receptor agonists stimulated no increase in vascular tube formation. These results indicate that the angiogenic effects of adenosine A(2A) receptor activation are, at least in part, caused by the suppression of TSP1 secretion.