Sinnathamby Tharsika, Yun JinTae, Clavet-Lanthier Marie-Élaine, Cheong Cheolho, Sirois Martin G
Research Center, Montreal Heart Institute, Montréal, Canada; Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Canada.
J Cell Biochem. 2015 Jan;116(1):45-57. doi: 10.1002/jcb.24941.
A key feature in the induction of pathological angiogenesis is that inflammation precedes and accompanies the formation of neovessels as evidenced by increased vascular permeability and the recruitment of inflammatory cells. Previously, we and other groups have shown that selected growth factors, namely vascular endothelial growth factor (VEGF) and angiopoietins (Ang1 and Ang2) do not only promote angiogenesis, but can also induce inflammatory response. Herein, given a pro-inflammatory environment, we addressed the individual capacity of VEGF and angiopoietins to promote the formation of mature neovessels and to identify the different types of inflammatory cells accompanying the angiogenic process over time. Sterilized polyvinyl alcohol (PVA) sponges soaked in growth factor-depleted Matrigel mixed with PBS, VEGF, Ang1, or Ang2 (200 ng/200 µl) were subcutaneously inserted into anesthetized mice. Sponges were removed at day 4, 7, 14, or 21 post-procedure for histological, immunohistological (IHC), and flow cytometry analyses. As compared to PBS-treated sponges, the three growth factors promoted the recruitment of inflammatory cells, mainly neutrophils and macrophages, and to a lesser extent, T- and B-cells. In addition, they were more potent and more rapid in the recruitment of endothelial cells (ECs) and in the formation and maturation (ensheating of smooth muscle cells around ECs) of neovessels. Thus, the autocrine/paracrine interaction among the different inflammatory cells in combination with VEGF, Ang1, or Ang2 provides a suitable microenvironment for the formation and maturation of blood vessels.
病理性血管生成诱导过程中的一个关键特征是炎症先于新血管形成并伴随其形成，这可通过血管通透性增加和炎症细胞募集得以证明。此前，我们和其他研究小组已表明，特定的生长因子，即血管内皮生长因子（VEGF）和血管生成素（Ang1和Ang2）不仅能促进血管生成，还可诱导炎症反应。在此，鉴于存在促炎环境，我们探讨了VEGF和血管生成素促进成熟新血管形成的个体能力，并确定了血管生成过程中随时间出现的不同类型炎症细胞。将浸泡在不含生长因子的基质胶中并与PBS、VEGF、Ang1或Ang2（200 ng/200 μl）混合的无菌聚乙烯醇（PVA）海绵皮下植入麻醉小鼠体内。在术后第4、7、14或21天取出海绵进行组织学、免疫组织化学（IHC）和流式细胞术分析。与PBS处理的海绵相比，这三种生长因子促进了炎症细胞的募集，主要是中性粒细胞和巨噬细胞，在较小程度上还有T细胞和B细胞。此外，它们在募集内皮细胞（ECs）以及新血管的形成和成熟（ECs周围平滑肌细胞的包裹）方面更有效且更迅速。因此，不同炎症细胞之间与VEGF、Ang1或Ang2的自分泌/旁分泌相互作用为血管的形成和成熟提供了适宜的微环境。
