Desai Avani, Victor-Vega Cassandre, Gadangi Swathi, Montesinos M Carmen, Chu Charles C, Cronstein Bruce N
Department of Medicine, New York University School of Medicine, New York, New York 10016, USA.
Mol Pharmacol. 2005 May;67(5):1406-13. doi: 10.1124/mol.104.007807. Epub 2005 Jan 26.
Topical adenosine A2A 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 A2A receptor occupancy modulates expression of the antiangiogenic matrix protein thrombospondin 1 (TSP1). We therefore determined whether A2A 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 (CGS-21680), or 2-[2-(4-chlorophenyl)ethoxy]adenosine (MRE0094), selective A2A receptor agonists. TSP1 protein secretion was down-regulated after treatment with the A2A agonists CGS-21680 or MRE0094 in a dose-dependent manner (EC50 = 6.65 nM and 0.23 microM respectively). The selective A2A receptor antagonist 4-[2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl]phenol (ZM241385) but not the A1 and A2B receptor antagonists diphenylcyclopentylxanthine, enprofylline, and N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide (MRS1706) completely abrogated the A2A receptor agonist-mediated effect on TSP1. Vascular tube formation by HMVEC was increased by adenosine A2A receptor agonists in a dose-dependent fashion (EC50 = 0.1 microM for both), and this effect was reversed by the A2A antagonist. Moreover, in the presence of antibodies to TSP1 and CD36, the receptor for TSP1, the adenosine A2A receptor agonists stimulated no increase in vascular tube formation. These results indicate that the angiogenic effects of adenosine A2A receptor activation are, at least in part, caused by the suppression of TSP1 secretion.
局部应用的腺苷A2A受体激动剂可通过多种作用促进伤口愈合，其中包括增加微血管形成。对人脐静脉内皮细胞进行代表性差异分析的结果表明，A2A受体的占据可调节抗血管生成基质蛋白血小板反应蛋白1（TSP1）的表达。因此，我们确定A2A受体的占据是否通过调节TSP1分泌来刺激血管生成。用人微血管内皮细胞（HMVEC）分别单独用培养基、选择性A2A受体激动剂2-p-[2-羧乙基]苯乙胺-5'-N-乙基羧酰胺腺苷（CGS-21680）或2-[2-（4-氯苯基）乙氧基]腺苷（MRE0094）进行处理。用A2A激动剂CGS-21680或MRE0094处理后，TSP1蛋白分泌呈剂量依赖性下调（EC50分别为6.65 nM和0.23 microM）。选择性A2A受体拮抗剂4-[2-[7-氨基-2-（2-呋喃基）[1,2,4]三唑并-[2,3-a][1,3,5]三嗪-5-基氨基]乙基]苯酚（ZM241385）可完全消除A2A受体激动剂对TSP1的介导作用，而A1和A2B受体拮抗剂二苯基环戊基黄嘌呤、恩丙茶碱和N-（4-乙酰苯基）-2-[4-（2,3,6,7-四氢-2,6-二氧代-1,3-二丙基-1H-嘌呤-8-基）苯氧基]乙酰胺（MRS1706）则不能。腺苷A2A受体激动剂可使HMVEC形成的血管管腔呈剂量依赖性增加（两者的EC50均为0.1 microM），且该作用可被A2A拮抗剂逆转。此外，在存在抗TSP1抗体和TSP1的受体CD36（TSP1的受体）的情况下，腺苷A2A受体激动剂不会刺激血管管腔形成增加。这些结果表明，腺苷A2A受体激活的血管生成作用至少部分是由TSP1分泌的抑制引起的。
