Pericyte-specific deletion of ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature
Pericyte-specific deletion of ninjurin-1 induces fragile vasa vasorum formation and enhances intimal hyperplasia of injured vasculature
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DOI：
10.1152/ajpheart.00931.2020
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发表时间：
2021-06-01
影响因子：
4.8
通讯作者：
Kawabe, Jun-Ichi
中科院分区：
文献类型：
--
作者：
Horiuchi, Kiwamu;Kano, Kohei;Kawabe, Jun-Ichi
血管外膜异常包括血管畸形与动脉粥样硬化斑块的发展和易损性有关。然而，血管畸形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ninjurin-1（Ninj 1）是周细胞形成成熟新生血管的关键粘附分子。目的是使用周细胞特异性Ninf 1缺失小鼠模型来检查Ninj 1是否调节外膜血管生成并影响损伤血管的血管重塑。通过插入盘绕的金属丝损伤小鼠股动脉。血管损伤后4周，固定的动脉脱色。在三维视图中估计血管重塑，包括内膜增生和外膜微血管形成。通过异硫氰酸荧光素（FITC）-凝集素或FITC-葡聚糖从微血管外渗来评估血管脆性，包括血液渗漏。Ninj 1的表达增加，在周细胞血管损伤的反应。用他莫昔芬（Tam）处理NG 2-CreER/Ninjl（loxp）小鼠以诱导周细胞中Ninjl的缺失（Ninji KO）。TAM处理的NG 2-CreER或TAM未处理的NG 2-CreER/Ninj 1（loxp）小鼠用作对照。与对照组相比，Ninj 1 KO中内膜增生显著增强。在N/nf 1 KO中，血管渗漏显著增强。在Ninj 1 KO中，外膜中浸润的巨噬细胞数量增加，沿着炎性细胞因子的表达。总之，周细胞中Ninj 1的缺失诱导损伤血管的未成熟血管形成，并加剧外膜炎症和内膜增生。因此，Ninj 1有助于血管vasorum成熟的血管损伤和减少血管remodeling.NEW &值得注意的是，虽然异常的血管外膜vasorum与血管重塑，如动脉粥样硬化，血管畸形的机制及其在血管重塑中的作用还没有完全澄清。本研究提供了一系列新的证据，表明ninjurin-1有助于血管损伤过程中外膜微血管的成熟，并调节血管重塑。
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 Ninf1 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/Ninj1(loxp) mice were treated with tamoxifen (Tam) to induce deletion of Ninjl in pericyte (Ninji KO). Tam-treated NG2-CreER or Tam-nontreated NG2-CreER/Ninj1(loxp) mice were used as controls. Intimal hyperplasia was significantly enhanced in Ninj1 KO compared with controls. Vascular leakiness was significantly enhanced in N/nf1 KO. In Ninj1 KO, the number of infiltrated macrophages in adventitia was increased, along with the expression of inflammatory cytokines. In conclusion, deletion of Ninj1 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.NEW & NOTEWORTHY 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.