Matrix Metalloproteinase-1-mediated Up-regulation of Vascular Endothelial Growth Factor-2 in Endothelial Cells
Matrix Metalloproteinase-1-mediated Up-regulation of Vascular Endothelial Growth Factor-2 in Endothelial Cells
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DOI：
10.1074/jbc.m112.417451
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发表时间：
2013-01-04
影响因子：
4.8
通讯作者：
Schmid-Schoenbein, Geert W.
中科院分区：
文献类型：
--
作者：
Mazor, Rafi;Alsaigh, Tom;Schmid-Schoenbein, Geert W.
基质金属蛋白酶-1（MMP-1）是一种胶原酶，在细胞外基质和血管重塑、血管生成和肿瘤进展中具有高度活性。血管内皮生长因子受体2（VEGFR 2）是VEGF-A的主要受体，在内皮细胞上表达并促进细胞存活、增殖和其他功能。虽然MMP-1和VEGFR 2在许多正常和病理生理条件下共存，但MMP-1对细胞VEGFR 2的作用可以促进上述过程是未知的。在这项研究中，我们测试的假设，刺激内皮细胞MMP-1增加其水平的VEGFR 2。然后，增加的VEGFR 2可用于结合VEGF-A，导致反应增加。事实上，我们发现与活性MMP-1孵育的内皮细胞具有更高的VEGFR 2 mRNA和蛋白水平。此外，VEGF-A依赖的细胞内信号分子的磷酸化和内皮细胞增殖后MMP-1治疗升高。MMP-1可激活内皮细胞核因子-κ B（NF-κ B）通路（p65/RelA），这种反应依赖于蛋白酶激活受体-1（PAR-1）的激活。染色质免疫沉淀用于确认NF-κ B介导的VEGFR 2（KDR）基因的活性转录。MMP-1刺激后VEGFR 2的升高被PAR-1敲低和NF-κ B特异性抑制所抑制。我们认为MMP-1通过刺激PAR-1和激活NF-κ B B来促进VEGF 2的表达和内皮细胞的增殖。这些结果表明MMP-1可能引发或敏化内皮细胞功能的机制。
Matrix metalloproteinase-1 (MMP-1) is a collagenase that is highly active in extracellular matrix and vascular remodeling, angiogenesis, and tumor progression. Vascular endothelial growth factor receptor-2 (VEGFR2), the main receptor for VEGF-A, is expressed on endothelial cells and promotes cell survival, proliferation, and other functions. Although MMP-1 and VEGFR2 co-exist in many normal and pathophysiological conditions, the effect of MMP-1 on cellular VEGFR2 that can promote the above processes is unknown. In this study we test the hypothesis that stimulation of endothelial cells with MMP-1 increases their levels of VEGFR2. The increased VEGFR2 is then available to bind VEGF-A, resulting in increased response. Indeed we found that endothelial cells incubated with active MMP-1 had higher mRNA and protein levels of VEGFR2. Furthermore, VEGF-A-dependent phosphorylation of intracellular signaling molecules and endothelial proliferation were elevated after MMP-1 treatment. MMP-1 caused activation of the nuclear factor-kappa B (NF-kappa B) pathway (p65/RelA) in endothelial cells, and this response was dependent upon activation of protease activated receptor-1 (PAR-1). Chromatin immunoprecipitation was used to confirm NF-kappa B-mediated active transcription of the VEGFR2 (KDR) gene. Elevation in VEGFR2 after MMP-1 stimulation was inhibited by PAR-1 knockdown and NF-kappa B specific inhibition. We conclude that MMP-1 promotes VEGFR2 expression and proliferation of endothelial cells through stimulation of PAR-1 and activation of NF-kappa B. These results suggest a mechanism by which MMP-1 may prime or sensitize endothelial cell functions.