Degradation of soluble VEGF receptor-1 by MMP-7 allows VEGF access to endothelial cells
Degradation of soluble VEGF receptor-1 by MMP-7 allows VEGF access to endothelial cells
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DOI：
10.1182/blood-2008-08-172742
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发表时间：
2009-03-05
期刊：
影响因子：
20.3
通讯作者：
Ochiai, Atsushi
中科院分区：
文献类型：
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作者：
Ito, Ta-Kashi;Ishii, Genichiro;Ochiai, Atsushi
血管内皮生长因子（VEGF）信号在血管内皮细胞的生理和病理血管生成中起着关键作用。内皮细胞分泌可溶性VEGF受体-1（sVEGFR-1/sFlt-1），这是一种内源性VEGF抑制剂，可隔离VEGF并阻断其与VEGF受体的接触。这就提出了一个问题，即VEGF如何通过这种内源性VEGF陷阱到达内皮细胞上的膜受体，这是VEGF驱动的血管生成所需的一个步骤。在这里，我们发现基质金属蛋白酶-7（MMP-7）降解人sVEGFR-1，这增加了内皮细胞周围VEGF的生物利用度。利用人脐静脉内皮细胞（HUVECs）的管形成试验、迁移试验和免疫共沉淀试验，我们发现MMP-7降解sVEGFR-1可释放sVEGFR-1中的VEGF（165）亚型。MMP-7的存在消除了sVEGFR-1对VEGF诱导的HUVEC上VEGF受体-2磷酸化的抑制作用。这些数据表明，VEGF逃脱的螯合内皮sVEGFR-1和促进血管生成的MMP-7的存在下。（血。2009; 113：2363-2369）
Vascular endothelial growth factor (VEGF) signaling in endothelial cells serves a critical role in physiologic and pathologic angiogenesis. Endothelial cells secrete soluble VEGF receptor-1 (sVEGFR-1/sFlt-1), an endogenous VEGF inhibitor that sequesters VEGF and blocks its access to VEGF receptors. This raises the question of how VEGF passes through this endogenous VEGF trap to reach its membrane receptors on endothelial cells, a step required for VEGF-driven angiogenesis. Here, we show that matrix metalloproteinase-7 (MMP-7) degrades human sVEGFR-1, which increases VEGF bioavailability around the endothelial cells. Using a tube formation assay, migration assay, and coimmunoprecipitation assay with human umbilical vein endothelial cells (HUVECs), we show that the degradation of sVEGFR-1 by MMP-7 liberates the VEGF(165) isoform from sVEGFR-1. The presence of MMP-7 abrogates the inhibitory effect of sVEGFR-1 on VEGF-induced phosphorylation of VEGF receptor-2 on HUVECs. These data suggest that VEGF escapes the sequestration by endothelial sVEGFR-1 and promotes angiogenesis in the presence of MMP-7. (Blood. 2009; 113: 2363-2369)