Capillary morphogenesis gene 2 (CMG2) mediates growth factor-induced angiogenesis by regulating endothelial cell chemotaxis.
Capillary morphogenesis gene 2 (CMG2) mediates growth factor-induced angiogenesis by regulating endothelial cell chemotaxis.
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DOI：
10.1007/s10456-022-09833-w
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发表时间：
2022-08
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
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作者：
炭疽保护性抗原(PA)是一种有效的病理性血管生成抑制因子，其机制尚不清楚。在炭疽中毒中，PA与毛细血管形态发生基因2(CMG2)和肿瘤内皮标记物8(TEM8)相互作用。在这里，我们发现CMG2介导PA的抗血管生成作用，并且是生长因子诱导的趋化作用所必需的。使用CMG2和TEM8与天然配体相互作用的特异性抑制剂，以及CMG2或TEM8跨膜和细胞内结构域被破坏的小鼠，我们证明抑制CMG2，而不是TEM8，可以减少生长因子诱导的角膜血管生成。此外，当CMG2基因而不是TEM8基因被破坏时，PA的抗血管生成作用被取消。结合实验表明，在细胞外基质(ECM)蛋白中，CMG2具有广泛的配基特异性。体外实验表明，在人真皮微血管内皮细胞(HMVEC-d)网络形成试验中，PA活性需要CMG2(而不是TEM8)。值得注意的是，在微流控迁移分析中，阻断CMG2配体与PA或CRISPR基因敲除结合可以取消内皮细胞的趋化作用，但不能消除趋化运动。这些效应是通过抑制Rho来实现的。由于CMG2以ECM依赖的方式介导内皮细胞对肽生长因子的趋化反应，因此CMG2非常适合整合生长因子和ECM信号。因此，CMG2靶向是一种抑制血管生成的新方法。
Anthrax protective antigen (PA) is a potent inhibitor of pathological angiogenesis with an unknown mechanism. In anthrax intoxication, PA interacts with capillary morphogenesis gene 2 (CMG2) and tumor endothelial marker 8 (TEM8). Here we show that CMG2 mediates the antiangiogenic effects of PA and is required for growth-factor-induced chemotaxis. Using specific inhibitors of CMG2 and TEM8 interaction with natural ligand, as well as mice with the CMG2 or TEM8 transmembrane and intracellular domains disrupted, we demonstrate that inhibiting CMG2, but not TEM8 reduces growth-factor-induced angiogenesis in the cornea. Furthermore, the antiangiogenic effect of PA was abolished when the CMG2, but not the TEM8, gene was disrupted. Binding experiments demonstrated a broad ligand specificity for CMG2 among extracellular matrix (ECM) proteins. Ex vivo experiments demonstrated that CMG2 (but not TEM8) is required for PA activity in human dermal microvascular endothelial cell (HMVEC-d) network formation assays. Remarkably, blocking CMG2-ligand binding with PA or CRISPR knockout abolishes endothelial cell chemotaxis but not chemokinesis in microfluidic migration assays. These effects are phenocopied by Rho inhibition. Because CMG2 mediates the chemotactic response of endothelial cells to peptide growth factors in an ECM-dependent fashion, CMG2 is well-placed to integrate growth factor and ECM signals. Thus, CMG2 targeting is a novel way to inhibit angiogenesis.
影响因子：
2.7
作者：
Cao, Shugeng;Cryan, Lorna;Habeshian, Kaiane A.;Murillo, Catalina;Tamayo-Castillo, Giselle;Rogers, Michael S.;Clardy, Jon
通讯作者：
Clardy, Jon
影响因子：
9.8
作者：
Vink, Joy Yumiko;Charles-Horvath, Pelisa Cheryll;Kitajewski, Jan Krzysztof;Reeves, Claire Vech
通讯作者：
Reeves, Claire Vech
影响因子：
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作者：
Cryan LM;Habeshian KA;Caldwell TP;Morris MT;Ackroyd PC;Christensen KA;Rogers MS
通讯作者：
Rogers MS