Abstract：
OBJECTIVE: Vascular smooth muscle cell (VSMC) plasticity is tightly associated with the pathological process of vasculopathy. Blood vessel epicardial substance (Bves) has emerged as an important regulator of intracardiac vasculogenesis and organ homeostasis. However, the involvement and role of Bves in VSMC plasticity and neointimal lesion development remain unclear.
METHODS: We used an in vivo rat model of graft arteriosclerosis and in vitro PDGF-treated VSMCs and identified the novel VSMC contractile phenotype-related gene Bves using a transcriptomic analysis and literature search. In vitro knockdown and overexpression approaches were used to investigate the mechanisms underlying VSMC phenotypic plasticity. In vivo, VSMC-specific Bves overexpression in rat aortic grafts was generated to assess the physiological function of Bves in neointimal lesion development.
RESULTS: Here, we found that Bves expression was negatively regulated in aortic allografts in vivo and PDGF-treated VSMCs in vitro. The genetic knockdown of Bves dramatically inhibited, whereas Bves overexpression markedly promoted, the VSMC contractile phenotype. Furthermore, RNA sequencing unraveled a positive correlation between Bves and dual-specificity protein phosphatase 1 (Dusp1) expression in VSMCs. We found that Bves knockdown restrained Dusp1 expression, but enhanced p38MAPK and ERK1/2 activation, resulting in the loss of the VSMC contractile phenotype. In vivo, an analysis of a rat graft model confirmed that VSMC-specific Bves and Dusp1 overexpression in aortic allografts significantly attenuated neointimal lesion formation.
CONCLUSIONS: Bves maintains the VSMC contractile phenotype through Dusp1-dependent p38MAPK and ERK1/2 signaling, and protects against neointimal formation, underscoring the important role of Bves in preventing transplant vasculopathy.
METHODS: We used an in vivo rat model of graft arteriosclerosis and in vitro PDGF-treated VSMCs and identified the novel VSMC contractile phenotype-related gene Bves using a transcriptomic analysis and literature search. In vitro knockdown and overexpression approaches were used to investigate the mechanisms underlying VSMC phenotypic plasticity. In vivo, VSMC-specific Bves overexpression in rat aortic grafts was generated to assess the physiological function of Bves in neointimal lesion development.
RESULTS: Here, we found that Bves expression was negatively regulated in aortic allografts in vivo and PDGF-treated VSMCs in vitro. The genetic knockdown of Bves dramatically inhibited, whereas Bves overexpression markedly promoted, the VSMC contractile phenotype. Furthermore, RNA sequencing unraveled a positive correlation between Bves and dual-specificity protein phosphatase 1 (Dusp1) expression in VSMCs. We found that Bves knockdown restrained Dusp1 expression, but enhanced p38MAPK and ERK1/2 activation, resulting in the loss of the VSMC contractile phenotype. In vivo, an analysis of a rat graft model confirmed that VSMC-specific Bves and Dusp1 overexpression in aortic allografts significantly attenuated neointimal lesion formation.
CONCLUSIONS: Bves maintains the VSMC contractile phenotype through Dusp1-dependent p38MAPK and ERK1/2 signaling, and protects against neointimal formation, underscoring the important role of Bves in preventing transplant vasculopathy.
摘要：
目的：血管平滑肌细胞(VSMC)可塑性与血管病变的病理过程密切相关。血管心外膜物质（Bves）已成为心内血管发生和器官稳态的重要调节剂。然而,Bves在VSMC可塑性和新内膜病变发展中的参与和作用尚不清楚。
方法：我们使用移植物动脉硬化和体外PDGF处理的VSMC的体内大鼠模型，并通过转录组学分析和文献检索鉴定了新的VSMC收缩表型相关基因Bves。使用体外敲低和过表达方法来研究VSMC表型可塑性的潜在机制。在体内,在大鼠主动脉移植物中产生VSMC特异性Bves过表达，以评估Bves在新内膜病变发展中的生理功能。
结果：这里，我们发现Bves的表达在体内主动脉移植物和体外PDGF处理的VSMC中负向调节。Bves的基因敲除显著抑制,而Bves过表达显着促进，VSMC收缩表型。此外，RNA测序揭示了VSMC中Bves与双特异性蛋白磷酸酶1（Dusp1）表达之间的正相关关系。我们发现Bves敲低抑制了Dusp1的表达，但增强p38MAPK和ERK1/2激活，导致VSMC收缩表型的丧失。在体内,对大鼠移植模型的分析证实，主动脉同种异体移植物中VSMC特异性Bves和Dusp1的过表达显着减轻了新内膜病变的形成。
结论：Bves通过Dusp1依赖性p38MAPK和ERK1/2信号维持VSMC收缩表型，并防止新内膜形成，强调Bves在预防移植血管病变中的重要作用。
方法：我们使用移植物动脉硬化和体外PDGF处理的VSMC的体内大鼠模型，并通过转录组学分析和文献检索鉴定了新的VSMC收缩表型相关基因Bves。使用体外敲低和过表达方法来研究VSMC表型可塑性的潜在机制。在体内,在大鼠主动脉移植物中产生VSMC特异性Bves过表达，以评估Bves在新内膜病变发展中的生理功能。
结果：这里，我们发现Bves的表达在体内主动脉移植物和体外PDGF处理的VSMC中负向调节。Bves的基因敲除显著抑制,而Bves过表达显着促进，VSMC收缩表型。此外，RNA测序揭示了VSMC中Bves与双特异性蛋白磷酸酶1（Dusp1）表达之间的正相关关系。我们发现Bves敲低抑制了Dusp1的表达，但增强p38MAPK和ERK1/2激活，导致VSMC收缩表型的丧失。在体内,对大鼠移植模型的分析证实，主动脉同种异体移植物中VSMC特异性Bves和Dusp1的过表达显着减轻了新内膜病变的形成。
结论：Bves通过Dusp1依赖性p38MAPK和ERK1/2信号维持VSMC收缩表型，并防止新内膜形成，强调Bves在预防移植血管病变中的重要作用。
