Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation

Abstract

Angiopoietin (Ang) signaling plays a role in angiogenesis and remodeling of blood vessels through the receptor tyrosine kinase Tie2, which is expressed on blood vessel endothelial cells (BECs). Recently it has been shown that Ang-2 is crucial for the formation of lymphatic vasculature and that defects in lymphangiogenesis seen in Ang-2 mutant mice are rescued by Ang-1. These findings suggest important roles for Ang signaling in the lymphatic vessel system; however, Ang function in lymphangiogenesis has not been characterized. In this study, we reveal that lymphatic vascular endothelial hyaluronan receptor 1-positive (LYVE-1 ؉ ) lymphatic endothelial cells (LECs) express Tie2 in both embryonic and adult settings, indicating that Ang signaling occurs in lymphatic vessels. Therefore, we examined whether Ang-1 acts on in vivo lymphatic angiogenesis and in vitro growth of LECs. A chimeric form of Ang-1, cartilage oligomeric matrix protein (COMP)-Ang-1, promotes in vivo lymphatic angiogenesis in mouse cornea. Moreover, we found that COMP-Ang-1 stimulates in vitro colony formation of LECs. These Ang-1-induced in vivo and in vitro effects on LECs were suppressed by soluble Tie2-Fc fusion protein, which acts as an inhibitor by sequestering Ang-1. On the basis of these observations, we propose that Ang signaling regulates lymphatic vessel formation through Tie2. IntroductionSeveral endothelial cell growth factors have thus far been identified as essential for vascular development, based primarily on genetargeting approaches. Among these factors, members of the angiopoietin (Ang) family are ligands for the receptor tyrosine kinase Tie2. 1,2 The first member of the family, Ang-1, activates Tie2 receptors expressed on vascular endothelial cells and functions as a positive regulator of angiogenesis and of remodeling and stabilization of blood vessels. 3 In contrast, the second member of the Ang family, Ang-2, plays a role in the context of vessel regression as a negative regulator of angiogenesis by blocking Tie2 activation. 4 Loss of function assays in mice have revealed that Ang-1 is essential for embryonic vascular development, 3 whereas Ang-2 is dispensable for embryonic angiogenesis but required for normal postnatal vascular remodeling. 5 These findings indicate different roles for Ang-1 and Ang-2 in blood vessel formation.The recent discovery of lymphatic endothelial cell (LEC) markers and factors regulating the development of lymphatic vessels has shed new light on the molecular mechanisms underlying lymphangiogenesis. 6,7 More recent findings from mice with targeted mutations in Ang-2 indicate that Ang-2 loss results in profound defects in patterning and function of the lymphatic vasculature, indicating that Ang-2 is crucial for lymphatic vessel development. 5 Interestingly, defects in lymphatics seen in Ang-2 Ϫ/Ϫ mice are completely rescued by Ang-1, suggesting a possible role for Ang in lymphangiogenesis. Moreover, this finding suggests an important role for Ang signaling in the formation of the lymphatic vessel sy...

Pathways Targeting Tumor Lymphangiogenesis

“…Importantly, VEGF-A also induced active proliferation of VEGFR-2-expressing tumor-associated lymphatic vessels in a multi-step skin carcinogenesis model, leading to enhanced tumor metastasis to the sentinel and distant lymph nodes (11). Angiopoietin-1, an activating ligand for the endothelial-specific receptor tyrosine kinase Tie2, induces lymphangiogenesis in the mouse cornea and, after adenoviral gene transfer, in other adult mouse tissues (23,24). Treatment with soluble VEGFR-3 inhibited the effects of virally delivered angiopoietin-1 in mice, indicating that angiopoietin-1 also acts indirectly via the VEGFR-3 pathway (24).…”

Advances in the research on lymphangiogenesis in carcinoma tissues (Review)

“…Ang-1 positively regulates vascular remodeling and stability, but Ang-2 has an antagonistic effect. Previous studies showed that Ang-1 is able to facilitate the growth of lymphatic vessels via ʻbudding̛, and this effect can be suppressed by transfection of the soluble protein VEGFR-3, indicating that Ang-1 acts via the VEGF-C/VEGF-D/VEGFR-3 signaling pathways (29). Although no reports are currently available on the Ang-2-mediated facilitation of lymphangiogenesis, clinical trials in gastric cancer indicated that Ang-2 is related to tumor lymph node metastasis (30).…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…Three members of the Angiopoietin family (Ang1, Ang2, and Ang3/4) are ligands for the Tie1 and/or Tie2 receptor tyrosine kinases, which are expressed both in blood vascular and lymphatic endothelia (Iljin et al 2002;Morisada et al 2005;Tammela et al 2005b). Ang1 can activate both Tie1 and Tie2 that appear as preformed heteromeric complexes between the two receptor molecules (Saharinen et al 2005).…”

“…Ang1 can activate both Tie1 and Tie2 that appear as preformed heteromeric complexes between the two receptor molecules (Saharinen et al 2005). Overexpression of Ang1 in adult mice stimulates lymphatic endothelial cell proliferation and promotes vessel enlargement and generation of new sprouts (Morisada et al 2005;Tammela et al 2005b). Ang2 is required for postnatal blood vascular remodeling and proper development of the lymphatic vasculature.…”