Department of Biochemistry, Asahikawa Medical University, Asahikawa, Japan.
Division of Cardiovascular, Respiratory, and Neurology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
Am J Physiol Heart Circ Physiol. 2021 Jun 1;320(6):H2438-H2447. doi: 10.1152/ajpheart.00931.2020. Epub 2021 May 7.
Adventitial abnormalities including enhanced vasa vasorum malformation are associated with development and vulnerability of atherosclerotic plaque. However, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. We recently reported that ninjurin-1 (Ninj1) is a crucial adhesion molecule for pericytes to form matured neovessels. The purpose is to examine if Ninj1 regulates adventitial angiogenesis and affects the vascular remodeling of injured vessels using pericyte-specific deletion mouse model. Mouse femoral arteries were injured by insertion of coiled wire. Four weeks after vascular injury, fixed arteries were decolorized. Vascular remodeling, including intimal hyperplasia and adventitial microvessel formation were estimated in a three-dimensional view. Vascular fragility, including blood leakiness was estimated by extravasation of fluorescein isothiocyanate (FITC)-lectin or FITC-dextran from microvessels. Ninj1 expression was increased in pericytes in response to vascular injury. NG2-CreER/ mice were treated with tamoxifen (Tam) to induce deletion of in pericyte ( KO). Tam-treated NG2-CreER or Tam-nontreated NG2-CreER/ mice were used as controls. Intimal hyperplasia was significantly enhanced in KO compared with controls. Vascular leakiness was significantly enhanced in KO. In KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of in pericytes induces the immature vasa vasorum formation of injured vasculature and exacerbates adventitial inflammation and intimal hyperplasia. Thus, Ninj1 contributes to the vasa vasorum maturation in response to vascular injury and to reduction of vascular remodeling. Although abnormalities of adventitial vasa vasorum are associated with vascular remodeling such as atherosclerosis, the mechanisms of vasa vasorum malformation and its role in vascular remodeling have not been fully clarified. The present study provides a line of novel evidence that ninjurin-1 contributes to adventitial microvascular maturation during vascular injury and regulates vascular remodeling.
血管外膜异常包括增强的血管生成异常与动脉粥样硬化斑块的发生和易损性有关。然而，血管生成异常的机制及其在血管重塑中的作用尚未完全阐明。我们最近报道，Ninj1（神经生长因子诱导蛋白 1）是周细胞形成成熟新生血管的关键黏附分子。本研究旨在使用周细胞特异性敲除小鼠模型，研究 Ninj1 是否调节血管外膜血管生成并影响损伤血管的血管重塑。通过插入螺旋丝来损伤小鼠股动脉。血管损伤 4 周后，对固定的血管进行脱色。在三维视图中评估血管重塑，包括内膜增生和血管外膜微血管形成。通过荧光素异硫氰酸酯（FITC）-凝集素或 FITC-葡聚糖从微血管中外渗来评估血管脆性，包括血液渗漏。血管损伤后，Ninj1 在周细胞中表达增加。用他莫昔芬（Tam）处理 NG2-CreER/小鼠以诱导周细胞中缺失（KO）。将用 Tam 处理的 NG2-CreER/或未用 Tam 处理的 NG2-CreER/小鼠用作对照。与对照组相比，KO 组的内膜增生明显增强。KO 组的血管通透性明显增强。在 KO 组，血管外膜浸润的巨噬细胞数量增加，同时炎症细胞因子的表达增加。总之，周细胞中缺失诱导损伤血管不成熟的血管生成异常，并加重血管外膜炎症和内膜增生。因此，Ninj1 有助于血管损伤时血管生成异常的成熟和血管重塑的减少。尽管血管外膜血管生成异常与血管重塑如动脉粥样硬化有关，但血管生成异常的机制及其在血管重塑中的作用尚未完全阐明。本研究提供了一条新的证据表明，神经生长因子诱导蛋白 1 在血管损伤时有助于血管外膜微血管成熟，并调节血管重塑。
