Abstract 995: Angiopoietin-Like Protein 2 Induces Angiogenesis, Lymphangiogenesis, and Leukocytes Recruitment, Resulting in Enhancement of Inflammation
Angiopoietin through Tie2 tyrosine kinase receptor plays an important role in vascular remodeling. We and several other groups have identified angiopoietin-like proteins (Angptls) containing a coiled-coil domain and a fibrinogen-like domain, both of which are characteristic of angiopoietins. Early reports revealed that Angptls do not bind to Tie2, however some Angptls also function to modulate angiogenesis, suggesting that Angptls may be involved in various pathological conditions. Here, we revealed that the small Rho-GTPase Rac was activated diffusely at the plasma membrane, followed by lamellipodial protrusion and membrane ruffling in Angptl2-stimulated endothelial cells. Furthermore, in vitro migration assays revealed that Angptl2 promoted the motility of vascular blood endothelial cells (BECs), lymphatic endothelial cells (LECs), monocytes and granulocytes. We next generated transgenic mice overexpressing Angptl2 in the skin (K14-Angptl2 mice) to investigate the biological functions of Angptl2 in vivo. K14-Angptl2 mice exhibited increases in density and size of blood and lymphatic vessel. Morphological analysis with lectin staining revealed that enlarged blood vessels were postcapillary venules and venules, where are the segment most likely to sprout during angiogenesis and the site of inflammation-induced plasma leak. Actually, the vasculature in K14-Angptl2 mice was more leaky compared to controls under inflammation, but not baseline conditions. These findings suggested the Angptl2-induced leukocytes and monocytes in K14-Angptl2 mice might act as sources for various inflammatory cytokines, and therefore Angptl2-induced vasculature is more leaky under inflammation condition. In summary, Angptl2 promoted angiogenesis, lymphangiogenesis, leukocyte and monocytes recruitment, and the vascular leakiness under the inflammation. Since such events are known to play an important role in various pathogenesis, such as atherosclerosis and obesity. It may be of interest that the identification of the role of Angptl2 in atherosclerosis and obesity, because the Angptl3, Angptl4 and AGF/Angptl6 have been shown to involved in the pathogenesis of metabolic syndrome.