Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells
Crosstalk between neovessels and mural cells directs the site-specific expression of MT1-MMP to endothelial tip cells
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DOI：
10.1242/jcs.000679
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发表时间：
2007-05-01
影响因子：
4
通讯作者：
Seiki, Motoharu
中科院分区：
文献类型：
--
作者：
Yana, Ikuo;Sagara, Hiroshi;Seiki, Motoharu
膜锚定基质金属蛋白酶MT1-MMP（也称为Mmp14）在血管生成过程中起关键作用，但其在体内环境下时空调节的机制尚未明确。通过全挂免疫组织化学分析和将lacZ基因插入到Mmp14基因中，我们发现MT1-MMP在体内的血管表达主要局限于新毛细血管结构的发芽尖端，内皮细胞增殖和胶原降解在这里协调进行。在体外血管生成过程中，内皮细胞在辅助壁细胞存在或不存在的情况下被刺激进行新血管形成，位点特异性MT1-MMP表达被内皮细胞和血管平滑肌细胞（VSMC）之间的串扰所控制。当通过引入可溶性形式的受体酪氨酸激酶Tek来抑制VSMCs诱导的血管成熟时，MT1-MMP的分布不再局限于内皮尖端细胞，而是分布在体外和离体的整个新血管网络中。综上所述，这些数据表明，由内皮细胞/壁细胞相互作用协调的血管成熟将MT1-MMP的表达重定向到新生血管尖端，在那里蛋白酶调节血管发育前沿的基质重塑。
The membrane-anchored matrix metalloproteinase MT1-MMP (also known as Mmp14) plays a key role in the angiogenic process, but the mechanisms underlying its spatiotemporal regulation in the in vivo setting have not been defined. Using whole-mount immunohistochemical analysis and the lacZ gene inserted into the Mmp14 gene, we demonstrate that MT1-MMP vascular expression in vivo is confined largely to the sprouting tip of neocapillary structures where endothelial cell proliferation and collagen degradation are coordinately localized. During angiogenesis in vitro, wherein endothelial cells are stimulated to undergo neovessel formation in the presence or absence of accessory mural cells, site-specific MT1-MMP expression is shown to be controlled by crosstalk between endothelial cells and vascular smooth muscle cells (VSMC). When vessel maturation induced by VSMCs is inhibited by introducing a soluble form of the receptor tyrosine kinase Tek, MT1-MMP distribution is no longer restricted to the endothelial tip cells, but instead distributes throughout the neovessel network in vitro as well as ex vivo. Taken together, these data demonstrate that vascular maturation coordinated by endothelial cell/mural cell interactions redirects MT1-MMP expression to the neovessel tip where the protease regulates matrix remodeling at the leading edge of the developing vasculature.