Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
Angiogenesis. 2014 Jan;17(1):109-18. doi: 10.1007/s10456-013-9381-6. Epub 2013 Sep 8.
Macrophages show extreme heterogeneity and different subsets have been characterized by their activation route and their function. For instance, macrophage subsets are distinct by acting differently under pathophysiological conditions such as inflammation and cancer. Macrophages also contribute to angiogenesis, but the role of various specific subsets in angiogenesis has not been thoroughly investigated.
Matrigel supplemented with macrophage subsets [induced by IFNγ (M1), IL-4 (M2a) or IL-10 (M2c)] was injected subcutaneously in C57BL/6 J mice and analyzed by CD31 staining after 14 days. Increased numbers of endothelial cells and tubular structures were observed in M2-enriched plugs compared to control and other subsets. Additionally, more tubular structures formed in vitro in the presence of M2 macrophages or their conditioned medium. To identify a mechanism for the pro-angiogenic effect, gene expression of angiogenic growth factors was analyzed. Induced expression of basic fibroblast growth factor (Fgf2), insulin-like growth factor-1 (Igf1), chemokine (C-C motif) ligand 2 (Ccl2) and placental growth factor (Pgf) was observed in M2 macrophages. Using a blocking antibody of PlGF to inhibit M2c induced angiogenesis resulted in mildly reduced (40 %) tube formation whereas neutralization of FGF-2 (M2a) signaling by sFGFR1-IIIc affected tube formation by nearly 75 %.
These results indicate that macrophages polarized towards an M2 phenotype have a higher angiogenic potential compared to other subsets. Furthermore, we propose FGF signaling for M2a- and PlGF signaling for M2c-induced angiogenesis as possible working mechanisms, yet, further research should elucidate the exact mechanism for M2-induced angiogenesis.
巨噬细胞表现出极大的异质性，不同亚群根据其激活途径和功能进行了特征描述。例如，巨噬细胞亚群在炎症和癌症等病理生理条件下的作用不同，因此具有不同的特征。巨噬细胞也有助于血管生成，但各种特定亚群在血管生成中的作用尚未得到彻底研究。
在 C57BL/6J 小鼠中，将富含巨噬细胞亚群（由 IFNγ（M1）、IL-4（M2a）或 IL-10（M2c）诱导）的 Matrigel 皮下注射，并在 14 天后通过 CD31 染色进行分析。与对照组和其他亚群相比，M2 富集塞中观察到内皮细胞和管状结构数量增加。此外，在存在 M2 巨噬细胞或其条件培养基的情况下，体外形成更多的管状结构。为了确定促血管生成作用的机制，分析了血管生成生长因子的基因表达。在 M2 巨噬细胞中观察到碱性成纤维细胞生长因子（Fgf2）、胰岛素样生长因子-1（Igf1）、趋化因子（C-C 基序）配体 2（Ccl2）和胎盘生长因子（Pgf）的诱导表达。使用 PlGF 的阻断抗体抑制 M2c 诱导的血管生成导致管形成轻度减少（40%），而 FGF-2（M2a）信号的中和通过 sFGFR1-IIIc 影响管形成近 75%。
这些结果表明，极化到 M2 表型的巨噬细胞比其他亚群具有更高的血管生成潜力。此外，我们提出 FGF 信号转导用于 M2a 诱导的血管生成和 PlGF 信号转导用于 M2c 诱导的血管生成作为可能的作用机制，但需要进一步研究阐明 M2 诱导的血管生成的确切机制。
