Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration
Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration
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DOI：
10.1124/jpet.112.195446
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发表时间：
2012-11-01
影响因子：
3.5
通讯作者：
Yan, Chen
中科院分区：
文献类型：
--
作者：
Cai, Yujun;Knight, Walter E.;Yan, Chen
血管平滑肌细胞(SMC)的异常激活与动脉粥样硬化、支架内再狭窄、静脉移植物疾病和移植相关血管病变等多种血管疾病有关。长春西汀是长春花碱的衍生物，长期以来一直被用作脑血流增强剂，用于治疗认知障碍。然而，其在病理性血管重塑中的作用尚不清楚。在此，我们发现全身应用长春西汀显著减少了结扎损伤后颈动脉新生内膜的形成。长春西汀还可显著降低体外培养人大隐静脉外植体的自发性重塑。在培养的SMC中，长春西汀呈剂量依赖性地抑制细胞增殖，并导致细胞周期停滞于G(1)期，这与细胞周期蛋白D1降低和p27(Kip1)水平升高有关。此外，二维移行实验和三维主动脉中膜侵袭实验表明，长春西汀剂量依赖性地抑制了血小板衍生生长因子(PDGF)刺激的SMC迁移。此外，长春西汀显著减少PDGF诱导的I型胶原和纤维连接蛋白的表达。值得注意的是，长春西汀特异性地抑制了PDGF刺激的细胞外信号调节激酶1/2(ERK1/2)的磷酸化，而不是蛋白激酶B。长春西汀显著抑制细胞内反应性氧化物种(ROS)的产生，这在很大程度上介导了长春西汀对ERK1/2激活和SMC生长的抑制作用。综上所述，我们的结果揭示了长春西汀至少部分通过抑制SMC中ROS的产生和ERK1/2的激活来减轻新生内膜增生和病理性血管重塑。鉴于长春西汀的安全性，这项研究为长春西汀在增殖性血管疾病中的治疗潜力提供了洞察力。
Abnormal vascular smooth muscle cell (SMC) activation is associated with various vascular disorders such as atherosclerosis, in-stent restenosis, vein graft disease, and transplantation-associated vasculopathy. Vinpocetine, a derivative of the alkaloid vincamine, has long been used as a cerebral blood flow enhancer for treating cognitive impairment. However, its role in pathological vascular remodeling remains unexplored. Herein, we show that systemic administration of vinpocetine significantly reduced neointimal formation in carotid arteries after ligation injury. Vinpocetine also markedly decreased spontaneous remodeling of human saphenous vein explants in ex vivo culture. In cultured SMCs, vinpocetine dose-dependently suppressed cell proliferation and caused G(1)-phase cell cycle arrest, which is associated with a decrease in cyclin D1 and an increase in p27(Kip1) levels. In addition, vinpocetine dose-dependently inhibited platelet-derived growth factor (PDGF)-stimulated SMC migration as determined by the two-dimensional migration assays and three-dimensional aortic medial explant invasive assay. Moreover, vinpocetine significantly reduced PDGF-induced type I collagen and fibronectin expression. It is noteworthy that PDGF-stimulated phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), but not protein kinase B, was specifically inhibited by vinpocetine. Vinpocetine powerfully attenuated intracellular reactive oxidative species (ROS) production, which largely mediates the inhibitory effects of vinpocetine on ERK1/2 activation and SMC growth. Taken together, our results reveal a novel function of vinpocetine in attenuating neointimal hyperplasia and pathological vascular remodeling, at least partially through suppressing ROS production and ERK1/2 activation in SMCs. Given the safety profile of vinpocetine, this study provides insight into the therapeutic potential of vinpocetine in proliferative vascular disorders.