Vascular Adventitial Fibroblasts-Derived FGF10 Promotes Vascular Smooth Muscle Cells Proliferation and Migration in vitro and the Neointima Formation in vivo.
Vascular Adventitial Fibroblasts-Derived FGF10 Promotes Vascular Smooth Muscle Cells Proliferation and Migration in vitro and the Neointima Formation in vivo.
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DOI：
10.2147/jir.s305204
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发表时间：
2021
影响因子：
4.5
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Chen Y;Chen Y;Jiang X;Shi M;Yang Z;Chen Z;Hua X;Chen J;Wang Y
血管损伤时血管外膜成纤维细胞(VAFs)的激活对中膜血管平滑肌细胞(VSMCs)的增殖、迁移和随后的新生内膜形成有重要作用。成纤维细胞生长因子(FGFs)等多种因子可调控VSMC的生长、增殖和表型转换，提示FGFs可能作为旁分泌信号调节VSMC的功能。然而，对信号分子(S)及其作用机制知之甚少。本研究旨在确定哪些成纤维细胞生长因子家族成员以及如何参与血管内皮生长因子介导的血管重构。采用定量聚合酶链式反应、免疫印迹和免疫组织化学方法观察FGF10和FGFR2在损伤血管组织中的时空表达。在共培养体系中进行VSMCs的增殖和迁移实验。用Western印迹、免疫组织化学和免疫荧光检测信号通路的激活情况。苏木精-伊红染色和免疫荧光染色观察外源性FGF10和siFGF10对新生内膜形成的影响。FGF10和FGFR2的表达在伤后3d至14d逐渐增加。损伤后FGF10在外膜显著上调，FGFR2在中膜和新生内膜均有表达。在体外，FGF10在血管内皮细胞中的表达最为显著，而FGFR2在VSMCs中的表达显著。两者均受PDGF调控。VAF与VSMCs体外共培养结果表明，VAF来源的FGF10可促进VSMCs的增殖和迁移。PDGF可协同增强这一过程。VAF来源的FGF10可以显著激活VSMC中的FGFR2，进而显著激活下游的MAPK/PI3K-AKT信号通路。外源性FGF10促进新生内膜形成，而siFGF10抑制新生内膜形成。VAFs来源的FGF10促进VSMCs的增殖、迁移和新生内膜的形成，FGF10-FGFR2信号通路激活MAPK/PI3K-AKT通路，PDGF协同增强FGF10信号通路。
Activation of vascular adventitial fibroblasts (VAFs) upon vascular injury contributes greatly to the medial vascular smooth muscle cells (VSMCs) proliferation, migration and the subsequent neointima formation. A number of factors including fibroblast growth factors (FGFs) have been shown to control VSMC growth, proliferation and phenotypic switching, suggesting that they may function as paracrine signals for VAFs to modulate VSMCs functions. However, little is known about the signaling molecule(s) and its mechanism of action. This study is set to identify which and how FGF family members are involved in VAFs mediated vascular remodeling. We used qPCR, Western blot and Immunohistochemistry to observe the spatiotemporal expression of FGF10 and FGFR2 in injured vascular tissue. The proliferation and migration assays of VSMCs were performed in a co-culture system. The activation of signaling pathway was detected by Western blot, immunohistochemistry and immunofluorescence. Hematoxylin-eosin and immunofluorescence were used to assess the effects of exogenous FGF10 and siFGF10 on the neointima formation. The expression of FGF10 and FGFR2 were increased from day 3 through day 14 post injury. FGF10 was significantly upregulated in adventitia, and FGFR2 was detected in both media and neointima after injury. In vitro, FGF10 was most prominently expressed in VAFs and FGFR2 was significantly expressed in VSMCs. Both were regulated by PDGF. Co-culture of VAFs and VSMCs in vitro showed that VAF-derived FGF10 promoted the proliferation and migration of VSMCs. PDGF could synergistically enhance the process. VAF-derived FGF10 can significantly activate the FGFR2 in VSMCs and furthermore significantly activate the downstream MAPK/PI3K-AKT signaling pathways. Delivery of exogenous FGF10 potentiated the neointima formation, while siFGF10 attenuated the neointima formation. VAFs-derived FGF10 promoted the proliferation and migration of VSMCs and neointima formation, and FGF10-FGFR2 signaling triggered the activation of MAPK/PI3K-AKT pathways in VSMCs and PDGF synergistically amplified FGF10 signaling.