背景和目的:管腔狭窄的主要原因之一是在医疗过程中引起的血管损伤。血管损伤破坏了内皮的完整性,引发血小板沉积,白细胞募集,和炎症因子的释放。这个,反过来,诱导血管平滑肌细胞(VSMC)的增殖,导致新内膜形成。然而,损伤后VSMC增殖的分子机制尚不清楚.KIF11通过在有丝分裂中期形成双极纺锤体来调节细胞周期至关重要。此过程可能有助于血管损伤后的VSMC增殖和新内膜形成。然而,KIF11在VSMC中的功能尚未阐明。本研究旨在探讨KIF11在调节VSMCs周期进展和增殖中的作用和机制。方法:对小鼠颈动脉损伤模型的转录组测序数据和PDGF-BB诱导的VSMCs的细胞转录组数据进行生物学分析后,我们发现了一个潜在的靶基因,KIF11可能在血管损伤中起关键作用。然后,我们建立了血管损伤模型,以研究KIF11表达和活性的变化如何影响体内VSMCs的增殖和新内膜形成。此外,我们使用siRNA和特异性抑制剂抑制体外培养的VSMCs中KIF11的表达和活性,以研究VSMCs周期进展和增殖的潜在机制.结果:免疫组织化学和免疫荧光结果显示损伤血管中KIF11表达显著上调。腹腔注射KIF11特异性抑制剂,K858在血管损伤模型中部分抑制内膜增生。体外实验进一步证明PDGF-BB通过PI3K/AKT途径上调KIF11表达,并增强KIF11活性。KIF11表达和活性的抑制部分逆转了PDGF-BB对VSMC的促周期进展和促增殖作用。此外,KIF11过表达部分抵消了VSMC中通过抑制PI3K/AKT途径诱导的增殖停滞和细胞周期停滞。结论:我们的研究强调了KIF11在调节血管损伤后VSMCs的周期进展和增殖中的关键作用。对这些机制的全面了解可以为治疗血管狭窄的潜在治疗干预铺平道路。
Background and aims: One of the primary causes of lumen narrowing is vascular injury induced during medical procedures. Vascular injury disrupts the integrity of the endothelium, triggering platelet deposition, leukocyte recruitment, and the release of inflammatory factors. This, in turn, induces the proliferation of vascular smooth muscle cells (
VSMCs), leading to neointima formation. However, the molecular mechanism underlying VSMC proliferation following injury remains unknown. KIF11 is critical in regulating the cell cycle by forming bipolar spindles during mitotic metaphase. This process may contribute to
VSMCs proliferation and neointima formation following vascular injury. Yet, the function of KIF11 in
VSMCs has not been elucidated. This study aims to investigate the role and mechanisms of KIF11 in regulating
VSMCs cycle progression and proliferation. Methods: After conducting biological analysis of the transcriptome sequencing data from the mouse carotid artery injury model and the cell transcriptome data of PDGF-BB-induced VSMCs, we identified a potential target gene, KIF11, which may play a crucial role in vascular injury. Then we established a vascular injury model to investigate how changes in KIF11 expression and activity influence in vivo VSMCs proliferation and neointimal formation. In addition, we employed siRNA and specific inhibitors to suppress KIF11 expression and activity in VSMCs cultured in vitro to study the mechanisms underlying
VSMCs cycle progression and proliferation. Results: The results of immunohistochemistry and immunofluorescence indicate a significant upregulation of KIF11 expression in the injured vascular. The intraperitoneal injection of the KIF11 specific inhibitor, K858, partially inhibits intimal hyperplasia in the vascular injury model. In vitro experiments further demonstrate that PDGF-BB upregulates KIF11 expression through the PI3K/AKT pathway, and enhances KIF11 activity. Inhibition of both KIF11 expression and activity partially reverses the pro-cycle progression and pro-proliferation effects of PDGF-BB on VSMCs. Additionally, KIF11 overexpression partially counteracts the proliferation arrest and cell cycle arrest induced by inhibiting the PI3K/AKT pathway in VSMCs. Conclusion: Our study highlights the crucial role of KIF11 in regulating the cycle progression and proliferation of VSMCs after vascular injury. A comprehensive understanding of these mechanisms could pave the way for potential therapeutic interventions in treating vascular stenosis.