A2B adenosine receptor dampens hypoxia-induced vascular leak
A2B adenosine receptor dampens hypoxia-induced vascular leak
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DOI：
10.1182/blood-2007-10-117044
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发表时间：
2008-02-15
期刊：
影响因子：
20.3
通讯作者：
Eltzschig, Holger K.
中科院分区：
文献类型：
--
作者：
Eckle, Tobias;Faigle, Marion;Eltzschig, Holger K.
细胞外腺苷参与了对缺氧的适应，先前的研究表明它在血管反应中起核心作用。在这里，我们研究了单个腺苷受体（ARs: A1AR/A2AAR/A28AR/A3AR）在缺氧诱导的血管泄漏中的作用。初步分析研究显示，sirna介导的A2BAR抑制选择性地增加了体外缺氧反应中的内皮泄漏。同时，A2BAR(-/-)-小鼠环境缺氧（8%氧气，4小时，如肺：增加2.1 +/- 0.12倍）时，血管器官的血管通透性显著增加。相比之下，缺氧诱导的血管渗漏在A1AR（-/-）、A2AAR（-/-）或A3AR（-/-）缺陷小鼠中没有加重，这表明A2BAR具有一定程度的特异性。在野生型小鼠中的进一步研究表明，选择性A2BAR拮抗剂PSB1115导致缺氧相关血管渗漏的显著增加，而A2BAR拮抗剂BAY60-6583[2-[6-氨基-3,5-二氰-4-]4-（环丙基-氧基）-。苯[吡啶-2-基磺胺][乙酰胺]]治疗与缺氧引起的血管渗漏几乎完全逆转相关（例如，肺：2.0 +/- 0.21倍减少）。对骨髓嵌合A2BAR小鼠的研究表明，血管A2BAR在这种反应中起主要作用，而组织中性粒细胞的缺氧相关增加，至少部分是由表达A2BAR的造血细胞介导的。综上所述，这些研究为血管A2BAR信号作为缺氧相关血管渗漏的中心控制点提供了药理学和遗传学证据。
Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (ARs: A1AR/A2AAR/A28AR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR(-/-)-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 +/- 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR(-/-), A2AAR(-/-), or A3AR(-/-)-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 [2-[6-amino-3,5-dicyano-4-[4-(cyclopropylme- thoxy)-. phenyl]pyridin-2-ylsulfanyl]acetamide]) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 +/- 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxi-aassociated vascular leak.