Adventitial fibroblast-derived vascular endothelial growth factor promotes vasa vasorum-associated neointima formation and macrophage recruitment
Adventitial fibroblast-derived vascular endothelial growth factor promotes vasa vasorum-associated neointima formation and macrophage recruitment
复制标题
外膜成纤维细胞衍生的 VEGF 促进血管滋养管相关的新内膜形成和巨噬细胞募集。
DOI：
10.1093/cvr/cvz159
复制
发表时间：
2020-03-01
影响因子：
10.8
通讯作者：
Gao, Ping-Jin
中科院分区：
文献类型：
--
作者：
Li, Xiao-Dong;Hong, Mo-Na;Gao, Ping-Jin
旨在
血管外膜小血管为血管壁提供氧气和营养，但它是否调节血管疾病仍不清楚。我们以前已经表明，VEGF（血管内皮生长因子）的表达增加与巨噬细胞浸润。本研究旨在确定外膜成纤维细胞来源的VEGF是否通过巨噬细胞募集增加促进新生内膜形成的血管数量。
方法和结果
在大鼠球囊损伤模型中，血管计数增加，特别是在外膜，伴随细胞增殖和VEGF表达。内源性和PKH 26标记的外源性巨噬细胞主要分布在血管周围的外膜。有趣的是，雷珠单抗的血管周围递送优先集中在外膜中，导致新生内膜形成减少，同时血管计数和巨噬细胞浸润减少。腺病毒介导的VEGF过度表达的外膜成纤维细胞传递到外膜显着增强这些损伤后的病理变化。在Tie 2-cre/Rosa-LoxP-RFP小鼠中，钢丝损伤后外膜中的内皮细胞增加。用多光子激光扫描显微镜观察血管内巨噬细胞的滚动、粘附和迁移。此外，巨噬细胞的过继转移加速损伤诱导的新生内膜形成。VEGF-中和抗体给药也减弱了金属丝损伤诱导的新生内膜形成和巨噬细胞浸润。在原代培养的血管外膜成纤维细胞中，外源性VEGF以时间和剂量依赖的方式增加VEGF的表达和分泌。VEGF中和抗体和VEGFR 2抑制剂ZM 323881可阻断外膜成纤维细胞条件培养液促进内皮细胞血管生成、血管细胞粘附分子1表达和巨噬细胞粘附，并抑制VEGFR 2/ERK 1/2通路的激活。
结论
这些结果表明，外膜成纤维细胞衍生的VEGF在血管计数的增加中起着重要作用，血管计数的增加与巨噬细胞募集和新生内膜形成有关。
AIMS
Adventitial vasa vasorum provides oxygen and nourishment to the vascular wall, but whether it regulates vascular disease remains unclear. We have previously shown that an increased expression of VEGF (vascular endothelial growth factor) is associated with macrophage infiltration. This study aims to determine whether adventitial fibroblast-derived VEGF increases the number of vasa vasorum contributing to neointima formation through macrophage recruitment.
METHODS AND RESULTS
In rat balloon injury model, vasa vasorum count was increased particularly in the adventitia accompanied by cell proliferation and VEGF expression. Both endogenous and PKH26-labelled exogenous macrophages were mainly distributed in adventitia around vasa vasorum. Interestingly, perivascular delivery of Ranibizumab preferentially concentrated in adventitia resulted in a decrease of neointima formation with concurrent reduction of vasa vasorum count and macrophage infiltration. Adventitial fibroblasts with adenovirus-mediated VEGF overexpression delivered to the adventitia significantly enhanced these pathological changes after injury. In Tie2-cre/Rosa-LoxP-RFP mice, endothelial cells were increased in the adventitia after wire injury. By using multiphoton laser scanning microscopy, macrophage rolling, adhesion and transmigration were observed in vasa vasorum. Moreover, adoptive transfer of macrophages accelerated injury-induced neointima formation. VEGF-neutralizing antibody administration also attenuated wire injury-induced neointima formation and macrophage infiltration. In primary cultured adventitial fibroblasts, exogenous VEGF increased VEGF expression and secretion in a time and dose-dependent manner. Adventitial fibroblast-conditioned medium promoted endothelial cell angiogenesis, vascular cell adhesion molecule-1 expression and macrophage adhesion was blocked by VEGF-neutralizing antibody and VEGFR2 inhibitor ZM323881, which also inhibited activation of VEGFR2/ERK1/2 pathway.
CONCLUSION
These results demonstrate that adventitial fibroblast-derived VEGF plays a significant role in the increase of vasa vasorum count which is involved in macrophage recruitment and neointima formation.