School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
Department of Nosocomial Infection, The First People's Hospital of Nantong, Nantong 226001, China.
Pharmacol Res. 2018 Jul;133:201-212. doi: 10.1016/j.phrs.2018.05.011. Epub 2018 May 20.
The RhoA/ROCK signaling pathway regulates cell morphology, adhesion, proliferation, and migration. In this study, we investigated the regulatory role of RhoA/ROCK signaling on PDGF-BB-mediated smooth muscle phenotypic modulation and vascular remodeling and clarified the molecular mechanisms behind these effects. PDGF-BB treatment induced the activation of RhoA, ROCK, PDGF-Rβ, and the expression of PDGF-Rβ in HA-VSMCs (human aortic vascular smooth muscle cells). PDGF-Rβ inhibition and RhoA suppression blocked PDGF-BB-induced RhoA activation and ROCK induction. In addition, PDGF-BB-mediated cell proliferation and migration were suppressed by PDGF-Rβ inhibition, RhoA suppression, and ROCK inhibition, suggesting that PDGF-BB promotes phenotypic modulation of HA-VSMCs by activating the RhoA/ROCK pathway via the PDGF receptor. Moreover, suppressing both ROCK1 and ROCK2 blocked cell cycle progression from G0/G1 to S phase by decreasing the transcription and protein expression of cyclin D1, CDK2, and CDK4 via JNK/c-Jun pathway, thus reducing cell proliferation in PDGF-BB-treated HA-VSMCs. ROCK1 deletion, rather than ROCK2 suppression, significantly inhibited PDGF-BB-induced migration by reducing the expression of vimentin and preventing the remodeling of vimentin and phospho-vimentin. Furthermore, ROCK1 deletion suppressed vimentin by inhibiting the phosphorylation of Smad2/3 and the nuclear translocation of Smad4. These findings suggested that ROCK1 and ROCK2 might play different roles in PDGF-BB-mediated cell proliferation and migration in HA-VSMCs. In addition, PDGF-BB and its receptor participated in neointima formation and vascular remodeling by promoting cell cycle protein expression via the JNK pathway and enhancing vimentin expression in a rat balloon injury model; effects that were inhibited by treatment with fasudil. Together, the results of this study reveal a novel mechanism through which RhoA/ROCK signaling regulates smooth muscle phenotypic modulation and vascular remodeling via the JNK pathway and vimentin cytoskeleton.
RhoA/ROCK 信号通路调节细胞形态、黏附、增殖和迁移。在这项研究中，我们研究了 RhoA/ROCK 信号对 PDGF-BB 介导的平滑肌表型调节和血管重塑的调节作用，并阐明了这些作用背后的分子机制。PDGF-BB 处理诱导 RhoA、ROCK、PDGF-Rβ 的激活和 HA-VSMCs（人主动脉血管平滑肌细胞）中 PDGF-Rβ 的表达。PDGF-Rβ 抑制和 RhoA 抑制阻断了 PDGF-BB 诱导的 RhoA 激活和 ROCK 诱导。此外，PDGF-Rβ 抑制、RhoA 抑制和 ROCK 抑制抑制了 PDGF-BB 介导的细胞增殖和迁移，表明 PDGF-BB 通过激活 PDGF 受体激活 RhoA/ROCK 通路促进 HA-VSMCs 的表型调节。此外，通过 JNK/c-Jun 通路降低细胞周期蛋白 D1、CDK2 和 CDK4 的转录和蛋白表达，抑制 ROCK1 和 ROCK2 的表达阻断了细胞从 G0/G1 期到 S 期的进展，从而减少了 PDGF-BB 处理的 HA-VSMCs 中的细胞增殖。ROCK1 缺失而非 ROCK2 抑制通过降低波形蛋白的表达并防止波形蛋白和磷酸化波形蛋白的重塑，显著抑制 PDGF-BB 诱导的迁移。此外，ROCK1 缺失通过抑制 Smad2/3 的磷酸化和 Smad4 的核易位抑制了波形蛋白的表达。这些发现表明，ROCK1 和 ROCK2 可能在 PDGF-BB 介导的 HA-VSMCs 细胞增殖和迁移中发挥不同的作用。此外，PDGF-BB 及其受体通过 JNK 通路促进细胞周期蛋白表达和增强在大鼠球囊损伤模型中的波形蛋白表达参与了新生内膜形成和血管重塑，而 fasudil 的治疗抑制了这些作用。总之，这项研究的结果揭示了一种新的机制，即 RhoA/ROCK 信号通过 JNK 通路和波形蛋白细胞骨架调节平滑肌表型调节和血管重塑。
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