Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice
Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice
复制标题
DOI：
10.1182/blood-2011-12-399659
复制
发表时间：
2012-06-28
期刊：
影响因子：
20.3
通讯作者：
Hattori, Koichi
中科院分区：
文献类型：
--
作者：
Tashiro, Yoshihiko;Nishida, Chiemi;Hattori, Koichi
纤溶酶原激活物抑制剂-1（派-1）是主要纤溶因子组织型纤溶酶原激活物的内源性抑制剂，具有促进和抑制血管生成的作用。然而，派-1的血管生成作用的生理作用和确切机制尚不清楚。在本研究中，我们报告说，药物抑制派-1促进血管生成和防止组织坏死的小鼠模型后肢缺血。组织再生的改善是由于循环和组织驻留的粒细胞-1标记物（Gr-1（+））中性粒细胞的扩增以及血管生成因子VEGF-A、造血生长因子试剂盒配体和G-CSF的释放增加。免疫组织化学分析表明派-1通道治疗动物的缺血腓肠肌组织中成纤维细胞生长因子-2（FGF-2）的量增加。去中和和基因敲除研究表明，组织再生的改善和循环和缺血组织驻留的Gr-1（+）中性粒细胞的增加依赖于组织型纤溶酶原激活剂和基质金属蛋白酶-9以及VEGF-A和FGF-2的激活。这些结果表明，药理学派-1抑制激活促血管生成FGF-2和VEGF-A途径，其协调嗜酸性粒细胞驱动的血管生成并诱导细胞驱动的血管再生，因此是缺血性疾病的潜在疗法。（血。2012;119（26）：6382-6393）
Plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of a major fibrinolytic factor, tissue-type plasminogen activator, can both promote and inhibit angiogenesis. However, the physiologic role and the precise mechanisms underlying the angiogenic effects of PAI-1 remain unclear. In the present study, we report that pharmacologic inhibition of PAI-1 promoted angiogenesis and prevented tissue necrosis in a mouse model of hind-limb ischemia. Improved tissue regeneration was due to an expansion of circulating and tissue-resident granulocyte-1 marker (Gr-1(+)) neutrophils and to increased release of the angiogenic factor VEGF-A, the hematopoietic growth factor kit ligand, and G-CSF. Immunohistochemical analysis indicated increased amounts of fibroblast growth factor-2 (FGF-2) in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated animals. Abneutralization and genetic knockout studies indicated that both the improved tissue regeneration and the increase in circulating and ischemic tissue-resident Gr-1(+) neutrophils depended on the activation of tissue-type plasminogen activator and matrix metalloproteinase-9 and on VEGF-A and FGF-2. These results suggest that pharmacologic PAI-1 inhibition activates the proangiogenic FGF-2 and VEGF-A pathways, which orchestrates neutrophil-driven angiogenesis and induces cell-driven revascularization and is therefore a potential therapy for ischemic diseases. (Blood. 2012;119(26):6382-6393)