title: Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10.
abstract: Angiopoietin (Ang)-2, a ligand of the receptor tyrosine kinase Tie2, is known to be involved in the regulation of embryonic lymphangiogenesis. However, the role of Ang-2 in postnatal pathological lymphangiogenesis, such as inflammation, is largely unknown. We used a combination of imaging, molecular, and cellular approaches to investigate whether Ang-2 is involved in inflammatory lymphangiogenesis. We observed strong and continuous expression of Ang-2 on newly generated lymphatic vessels for 2 wk in sutured corneas of BALB/c mice. This expression was concurrent with an increased number of lymphatic vessels. TNF-α expression also increased, with peak TNF-α expression occurring before peak Ang-2 expression was reached. In vitro experiments showed that TNF-α stimulates Ang-2 and Tie2 and ICAM-1 expression on human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BECs). Ang-2 alone did not affect the biological behavior of LECs, whereas Ang-2 combined with TNF-α significantly promoted the proliferation of LECs but not BECs. In mouse models, blockade of Ang-2 with L1-10, an Ang-2-specific inhibitor, significantly inhibited lymphangiogenesis but promoted angiogenesis. These results clearly indicate that Ang-2 acts as a crucial regulator of inflammatory lymphangiogenesis by sensitizing the lymphatic vasculature to inflammatory stimuli, thereby directly promoting lymphangiogenesis. The involvement of Ang-2 in inflammatory lymphangiogenesis provides a strong rationale for the exploitation of anti-Ang-2 treatment in the prevention and treatment of tumor metastasis and transplant rejection.
authors: Lymphology Center, Department of Plastic and Reconstructive Surgery, Shanghai 9th People's Hospital, China.
authors: Zhi-Xin
authors: ZX
authors: Yan
authors: Zhao-Hua
authors: ZH
authors: Jiang
authors: Ning-Fei
authors: NF
authors: Liu
mesh_terms: D042702:Angiopoietin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016510:Corneal Neovascularization / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D042583:Lymphangiogenesis / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; D000893:Anti-Inflammatory Agents; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha