Sema3G 通过 Nrp2/PlexinA1 激活 YAP，促进 VSMCs 的增殖和迁移。
Sema3G activates YAP and promotes VSMCs proliferation and migration via Nrp2/PlexinA1.
机构信息
Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Endocrinology and Metabolism, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai, China.
出版信息
Cell Signal. 2023 May;105:110613. doi: 10.1016/j.cellsig.2023.110613. Epub 2023 Jan 28.
BACKGROUND
Diabetes exacerbates neointima formation after vascular procedures, manifested by accelerated proliferation and migration of vascular smooth muscle cells (VSMCs). Semaphorin 3G (Sema3G), secreted mainly from endothelial cells (ECs), regulates various cellular functions and vascular pathologies. However, the function and potential mechanism of ECs-derived Sema3G in VSMCs under diabetic condition remain unclear.
OBJECTIVE
To investigate the role and the mechanism of ECs-derived Sema3G in the regulation of VSMCs proliferation and migration.
RESULTS
ECs-derived Sema3G promoted human aortic SMCs (HASMCs) cell cycle progression and proliferation. Sema3G upregulated the expression of MMP2 and MMP9, which might explain the increased HASMCs migration by Sema3G. Inhibition of Nrp2/PlexinA1 mitigated the effect of Sema3G on promoting HASMCs proliferation and migration. Mechanistically, Sema3G inhibited LATS1 and activated YAP via Nrp2/PlexinA1. Verteporfin, an FDA-approved YAP pathway inhibitor, counteracted Sema3G-induced cyclin E and cyclin D1 expression. Besides, Sema3G expression was upregulated in ECs of diabetic mouse aortas. Serum Sema3G level was increased in type 2 diabetic patients and mice. Moreover, compared to chow diet-fed mice, high-fat diet (HFD)-fed obese mice showed thicker neointima and higher Sema3G expression in vasculature after femoral injury.
CONCLUSIONS
Our results indicated that ECs-derived Sema3G under diabetic condition activated YAP and promoted HASMCs proliferation and migration via Nrp2/PlexinA1. Thus, inhibition of Sema3G may hold therapeutic potential against diabetes-associated intimal hyperplasia.
背景
糖尿病会加剧血管手术后的新生内膜形成，表现为血管平滑肌细胞（VSMCs）的增殖和迁移加速。Sema3G（Semaphorin 3G）主要由内皮细胞（ECs）分泌，调节各种细胞功能和血管病变。然而，糖尿病状态下 ECs 衍生的 Sema3G 对 VSMCs 的功能和潜在机制仍不清楚。
目的
研究 ECs 衍生的 Sema3G 在调节 VSMCs 增殖和迁移中的作用和机制。
结果
ECs 衍生的 Sema3G 促进人主动脉平滑肌细胞（HASMCs）细胞周期进程和增殖。Sema3G 上调了 MMP2 和 MMP9 的表达，这可能解释了 Sema3G 增加 HASMCs 迁移的原因。Nrp2/PlexinA1 的抑制减轻了 Sema3G 对促进 HASMCs 增殖和迁移的作用。机制上，Sema3G 通过 Nrp2/PlexinA1 抑制 LATS1 并激活 YAP。已被 FDA 批准的 YAP 通路抑制剂 Verteporfin 抵消了 Sema3G 诱导的 cyclin E 和 cyclin D1 的表达。此外，糖尿病小鼠主动脉 ECs 中 Sema3G 的表达上调。2 型糖尿病患者和小鼠的血清 Sema3G 水平升高。此外，与正常饮食喂养的小鼠相比，高脂肪饮食（HFD）喂养的肥胖小鼠在股动脉损伤后血管中出现更厚的新生内膜和更高的 Sema3G 表达。
结论
我们的结果表明，糖尿病状态下 ECs 衍生的 Sema3G 通过 Nrp2/PlexinA1 激活 YAP，促进 HASMCs 的增殖和迁移。因此，抑制 Sema3G 可能对糖尿病相关的内膜增生具有治疗潜力。
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