Ito Ta-Kashi, Ishii Genichiro, Saito Seiji, Yano Keiichi, Hoshino Ayuko, Suzuki Tasuku, Ochiai Atsushi
Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
Blood. 2009 Mar 5;113(10):2363-9. doi: 10.1182/blood-2008-08-172742. Epub 2008 Oct 30.
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.
血管内皮生长因子（VEGF）在内皮细胞中的信号传导在生理和病理性血管生成中起关键作用。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并阻止其与VEGF受体结合。这就提出了一个问题，即VEGF如何穿过这个内源性VEGF陷阱，到达内皮细胞上的膜受体，而这是VEGF驱动的血管生成所必需的一步。在这里，我们表明基质金属蛋白酶-7（MMP-7）可降解人sVEGFR-1，从而增加内皮细胞周围的VEGF生物利用度。通过使用人脐静脉内皮细胞（HUVECs）进行的管形成试验、迁移试验和免疫共沉淀试验，我们表明MMP-7对sVEGFR-1的降解可从sVEGFR-1中释放VEGF(165)亚型。MMP-7的存在消除了sVEGFR-1对HUVECs上VEGF诱导的VEGF受体-2磷酸化的抑制作用。这些数据表明，在MMP-7存在的情况下，VEGF可逃脱内皮sVEGFR-1的隔离并促进血管生成。
