RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis
RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis
复制标题
DOI：
10.1096/fj.09-145102
复制
发表时间：
2010-09-01
期刊：
影响因子：
4.8
通讯作者：
D'Amore, Patricia A.
中科院分区：
文献类型：
--
作者：
Bryan, Brad A.;Dennstedt, Emily;D'Amore, Patricia A.
小GTPase RhoA及其下游效应物ROCK1和ROCK2调节许多细胞过程，包括细胞运动、增殖、存活和通透性。据报道，Rho通路的药理抑制剂可阻断血管生成；然而，这种抑制的分子细节在很大程度上是未知的。我们证明血管内皮生长因子- a （VEGF）可以快速诱导内皮细胞（ECs）中的RhoA激活。此外，使用10 μ M Y-27632对ROCK1/2的药理学抑制（该化合物在内皮细胞中的IC50）强烈破坏了多能胚胎干细胞培养中的血管生成、体外视网膜外植体中vegf介导的再生血管生成以及vegf介导的体外内皮细胞管形成。此外，通过小干扰RNA敲除和小鼠杂合子敲除ROCK1和ROCK2，我们提供的数据表明vegf驱动的血管生成主要是通过ROCK2介导的。这些数据表明，Rho/ROCK信号在许多血管生成过程中是一个重要的介质，包括EC迁移、存活和细胞通透性，并表明Rho/ROCK抑制可能对血管生成相关疾病的治疗有用。-Bryan, b.a., Dennstedt， E., Mitchell， D., Walshe, t.e., Noma， K., Loureiro， R., Saint-Geniez， M.，RhoA/ROCK信号在vegf介导的血管生成的多个方面至关重要。中国生物医学工程学报，2009,32(4):444 - 444。www.fasebj.org
The small GTPase RhoA and its downstream effectors, ROCK1 and ROCK2, regulate a number of cellular processes, including cell motility, proliferation, survival, and permeability. Pharmacological inhibitors of the Rho pathway reportedly block angiogenesis; however, the molecular details of this inhibition are largely unknown. We demonstrate that vascular endothelial growth factor-A (VEGF) rapidly induces RhoA activation in endothelial cells (ECs). Moreover, the pharmacological inhibition of ROCK1/2 using 10 mu M Y-27632 (the IC50 for this compound in ECs) strongly disrupts vasculogenesis in pluripotent embryonic stem cell cultures, VEGF-mediated regenerative angiogenesis in ex vivo retinal explants, and VEGF-mediated in vitro EC tube formation. Furthermore, using small interfering RNA knockdown and mouse heterozygote knockouts of ROCK1 and ROCK2, we provide data indicating that VEGF-driven angiogenesis is largely mediated through ROCK2. These data demonstrate that Rho/ROCK signaling is an important mediator in a number of angiogenic processes, including EC migration, survival, and cell permeability, and suggest that Rho/ROCK inhibition may prove useful for the treatment of angiogenesis-related disorders.-Bryan, B. A., Dennstedt, E., Mitchell, D. C., Walshe, T. E., Noma, K., Loureiro, R., Saint-Geniez, M., Campaigniac, J.-P., Liao, J. K., D'Amore, P. A. RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis. FASEB J. 24, 3186 -3195 (2010). www.fasebj.org