A1 adenosine receptor activation promotes angiogenesis and release of VEGF from monocytes
A1 adenosine receptor activation promotes angiogenesis and release of VEGF from monocytes
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DOI：
10.1161/circresaha.107.150110
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发表时间：
2007-11-26
影响因子：
20.1
通讯作者：
Tucker, Amy L.
中科院分区：
文献类型：
--
作者：
Clark, Adam N.;Youkey, Rebecca;Tucker, Amy L.
腺苷是一种从缺血和缺氧组织中释放的促血管生成嘌呤核苷。在4种腺苷受体（AR）亚型(A(1)， A（2A)， A（2B）和A(3)）中，A(2)和A(3)先前与血管生成的调节有关。我们使用鸡绒毛膜尿囊膜（CAM）模型来确定A1 AR激活是否影响血管生成。我们克隆并对鸡AR亚型进行了药理学表征，以评估各种激动剂和拮抗剂的选择性。A(1) ar选择性拮抗剂N-6-环戊基腺苷（CPA, 100 nmol/L）对CAM的血管数量增加40% (P < 0.01)，可被A(1) ar选择性拮抗剂C-8-（N-甲基异丙基）-氨基-N-6-（5′-内羟）-内源性orbornan-2-yl-9-甲基腺苷（WRC-0571, 1 μ mol/L）阻断。选择性A(2A) AR激动剂不刺激CAM中的血管生成。在体外大鼠主动脉环血管生成模型中，包括共培养的内皮细胞、成纤维细胞和平滑肌细胞，50 nmol/L CPA没有直接刺激毛细血管形成；用CPA预处理的人单核细胞培养液使毛细血管形成增加48% （P < 0.05）。WRC-0571 （1.5 μ mol/L）或抗vegf抗体（1 μ g/mL）可阻断该作用。5 nmol/L的CPA刺激单核细胞中VEGF的释放增加1.7倍。这是首次发现A(1) AR激活诱导血管生成的研究。A(2) ar对内皮细胞的刺激导致细胞增殖和血管形成，A(2)和A(3) ar对炎症细胞的刺激调节血管生成因子的释放。我们得出结论，腺苷通过与多种细胞类型上的多种受体相互作用促进协调的血管生成反应。
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 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 A(1) AR-selective agonist N-6-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 A(1) AR-selective antagonist C-8-( N- methylisopropyl)-amino-N-6-(5'-endohydroxy)-endonorbornan-2-yl-9-methyladenine (WRC-0571; 1 mu 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% (P < 0.05). This effect was blocked by WRC-0571 (1.5 mu mol/L) or anti-VEGF antibody (1 mu 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.