Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells
Microfibril-associate glycoprotein-2 (MAGP-2) promotes angiogenic cell sprouting by blocking notch signaling in endothelial cells
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DOI：
10.1016/j.mvr.2008.01.001
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发表时间：
2008-05-01
影响因子：
3.1
通讯作者：
Schiemann, William P.
中科院分区：
文献类型：
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作者：
Albig, Allan R.;Becenti, Darryl J.;Schiemann, William P.
血管生成对血管微环境的组成高度敏感，然而，我们对血管微环境中调节血管生成的结构和基质细胞成分以及这些分子发挥作用的分子机制的理解仍然不完整。我们之前的研究结果描述了微纤维相关糖蛋白-2 （MAGP-2）的一种新的促血管生成活性，但没有解决其实现的分子机制。我们现在证明，MAGP-2通过拮抗内皮细胞中的Notch信号通路促进血管生成细胞的发芽。在瞬时转染的293T细胞中，MAGP-2降低了Notch敏感的Hes-1启动子在ECs中的基础表达和jagged1诱导的表达，并阻断了jagged1刺激的Notch1受体加工。有趣的是，MAGP-2对Notch信号的抑制似乎仅限于ECs，因为MAGP-2增加了异种细胞类型中的Hes-1启动子活性和Notch1受体加工。重要的是，Notch信号通路的组成性激活阻断了MAGP-2促进血管生成细胞发芽的能力，以及与血管生成相关的形态学改变。总的来说，这些观察结果表明，MAGP-2通过拮抗ECs中的Notch信号通路，促进体外血管生成细胞喷涌。(c) 2008爱思唯尔公司版权所有。
Angiogenesis is highly sensitive to the composition of the vascular microenvironment, however, our understanding of the structural and matricellular components of the vascular microenvironment that regulate angiogenesis and the molecular mechanisms by which these molecules function remains incomplete. Our previous results described a novel pro-angiogenic activity for Microfibril-Associated Glycoprotein-2 (MAGP-2), but did not address the molecular mechanism(s) by which this is accomplished. We now demonstrate that MAGP-2 promotes angiogenic cell sprouting by antagonizing Notch signaling pathways in endothelial cells. MAGP-2 decreased basal and jagged1 induced expression from the Notch sensitive Hes-1 promoter in ECs, and blocked Jagged1 stimulated Notch1 receptor processing in transiently transfected 293T cells. Interestingly, inhibition of Notch signaling by MAGP-2 seems to be restricted to ECs since MAGP-2 increased Hes-1 promoter activity and Notch1 receptor processing in heterologous cell types. Importantly, constitutive activation of the Notch signaling pathway blocked the ability of MAGP-2 to promote angiogenic cell sprouting, as well as morphological changes associated with angiogenesis. Collectively, these observations indicate that MAGP-2 promotes angiogenic cell spouting in vitro by antagonizing Notch signaling pathways in ECs. (c) 2008 Elsevier Inc. All rights reserved.