A pro-inflammatory signature mediates FGF2-induced angiogenesis
A pro-inflammatory signature mediates FGF2-induced angiogenesis
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DOI：
10.1111/j.1582-4934.2008.00415.x
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Presta, Marco
中科院分区：
文献类型：
--
作者：
Andres, German;Leali, Daria;Presta, Marco
成纤维细胞生长因子-2（FGF 2）是一种有效的血管生成生长因子。在这里，FGF 2刺激的微血管内皮细胞的基因表达谱显示，连同一个突出的促血管生成的配置文件，一个促炎的签名，其特征在于促炎细胞因子/趋化因子及其受体，内皮细胞粘附分子和类花生酸途径的成员的上调。实时定量PCR显示，大多数FGF 2诱导的炎症相关基因的早期诱导。因此，鸡胚绒毛尿囊膜（CAM）和鼠基质胶栓血管生成测定证明在FGF 2驱动的新血管形成区域中显著的单核细胞/巨噬细胞浸润。当将FGF 2刺激的内皮细胞的条件培养基（CM）递送到CAM上时获得类似的结果，表明FGF 2上调的化学引诱物介导炎症反应。重要的是，在表现出白细胞迁移缺陷的磷脂酰肌醇3-激酶-γ缺失小鼠或氯膦酸盐脂质体治疗的巨噬细胞耗竭小鼠中，FGF 2触发的新血管形成显著减少。此外，在CAM测定中，病毒泛趋化因子拮抗剂M3抑制由FGF 2刺激的内皮细胞的CM诱导的血管生成和炎症反应，并损害FGF 2驱动的新血管形成。这些发现指出炎性趋化因子作为FGF 2驱动的血管生成的早期介质，并表明炎性细胞在生长因子引起的新血管形成过程中的非冗余作用。
Fibroblast growth factor-2 (FGF2) is a potent angiogenic growth factor. Here, gene expression profiling of FGF2-stimulated microvascular endothelial cells revealed, together with a prominent pro-angiogenic profile, a pro-inflammatory signature characterized by the up-regulation of pro-inflammatory cytokine/chemokines and their receptors, endothelial cell adhesion molecules and members of the eicosanoid pathway. Real-time quantitative PCR demonstrated early induction of most of the FGF2-induced, inflammation-related genes. Accordingly, chick embryo chorioallantoic membrane (CAM) and murine Matrigel plug angiogenesis assays demonstrated a significant monocyte/macrophage infiltrate in the areas of FGF2-driven neovascularization. Similar results were obtained when the conditioned medium (CM) of FGF2-stimulated endothelial cells was delivered onto the CAM, suggesting that FGF2-upregulated chemoattractants mediate the inflammatory response. Importantly, FGF2-triggered new blood vessel formation was significantly reduced in phosphatidylinositol 3-kinase-gamma null mice exhibiting defective leucocyte migration or in clodronate liposome-treated, macrophage-depleted mice. Furthermore, the viral pan-chemokine antagonist M3 inhibited the angiogenic and inflammatory responses induced by the CM of FGF2-stimulated endothelial cells and impaired FGF2-driven neovascularization in the CAM assay. These findings point to inflammatory chemokines as early mediators of FGF2-driven angiogenesis and indicate a non-redundant role for inflammatory cells in the neovascularization process elicited by the growth factor.