Human Urinary Kallidinogenase Promotes Angiogenesis and Cerebral Perfusion in Experimental Stroke.
Human Urinary Kallidinogenase Promotes Angiogenesis and Cerebral Perfusion in Experimental Stroke.
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人尿激肽原酶促进实验性中风的血管生成和脑灌注
DOI：
10.1371/journal.pone.0134543
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Han L;Li J;Chen Y;Zhang M;Qian L;Chen Y;Wu Z;Xu Y;Li J
血管生成是缺血反应的关键恢复机制，促血管生成治疗可能对中风有益。越来越多的实验和临床证据表明，人尿碱二酚原酶（HUK）可改善脑卒中预后，但其潜在机制尚不清楚。本研究的目的是验证HUK在缺血后血管生成中的作用并确定相关的介质。在大鼠大脑中动脉闭塞（MCAO）模型中，我们证实HUK治疗可以改善脑卒中结局，表现为梗死面积减小和神经功能改善。值得注意的是，18F-FDG微pet扫描显示，HUK增强了MCAO处理后大鼠的脑灌注。此外，HUK促进缺血后血管生成，在HUK处理的MCAO小鼠中，血管密度增加，VEGF和apelin/APJ表达上调。在内皮细胞培养中，进一步证实了HUK诱导VEGF和apelin/APJ表达，以及ERK1/2磷酸化。选择性ERK1/2抑制剂U0126消除了这些变化。此外，APJ受体竞争拮抗剂F13A显著抑制huk诱导的VEGF表达。此外，在体外和体内，选择性缓激肽B1或B2受体拮抗剂存在时，HUK的血管生成功能被抑制。我们的研究结果表明，HUK治疗通过激活缓激肽B1和B2受体促进缺血后血管生成和脑灌注，这可能是通过ERK1/2依赖的方式增强VEGF和apelin/APJ的表达。
Angiogenesisis a key restorative mechanism in response to ischemia, and pro-angiogenic therapy could be beneficial in stroke. Accumulating experimental and clinical evidence suggest that human urinary kallidinogenase (HUK) improves stroke outcome, but the underlying mechanisms are not clear. The aim of current study was to verify roles of HUK in post-ischemic angiogenesis and identify relevant mediators. In rat middle cerebral artery occlusion (MCAO) model, we confirmed that HUK treatment could improve stroke outcome, indicated by reduced infarct size and improved neurological function. Notably, the 18F-FDG micro-PET scan indicated that HUK enhanced cerebral perfusion in rats after MCAO treatment. In addition, HUK promotespost-ischemic angiogenesis, with increased vessel density as well as up-regulated VEGF andapelin/APJ expression in HUK-treated MCAO mice. In endothelial cell cultures, induction of VEGF and apelin/APJ expression, and ERK1/2 phosphorylation by HUK was further confirmed. These changes were abrogated by U0126, a selective ERK1/2 inhibitor. Moreover, F13A, a competitive antagonist of APJ receptor, significantly suppressed HUK-induced VEGF expression. Furthermore, angiogenic functions of HUK were inhibited in the presence of selective bradykinin B1 or B2 receptor antagonist both in vitro and in vivo. Our findings indicate that HUK treatment promotes post-ischemic angiogenesis and cerebral perfusion via activation of bradykinin B1 and B2 receptors, which is potentially due to enhancement expression of VEGF and apelin/APJ in ERK1/2 dependent way.