Angiopoietin-1 promotes lymphatic sprouting and hyperplasia

Abstract

Angiopoietin 1 (Ang1), a ligand for the receptor tyrosine kinase Tie2, regulates the formation and stabilization of the blood vessel network during embryogenesis. In adults, Ang1 is associated with blood vessel stabilization and recruitment of perivascular cells, whereas Ang2 acts to counter these actions. Recent results from gene-targeted mice have shown that Ang2 is also essential for the proper patterning of lymphatic vessels and that Ang1 can be substituted for this function. In order to characterize the effects of the angiopoietins on lymphatic vessels, we employed viral vectors for overexpression of Ang1 in adult mouse tissues. We found that Ang1 activated lymphatic vessel endothelial proliferation, vessel enlargement, and generation of long endothelial cell filopodia that eventually fused, leading to new sprouts and vessel development. IntroductionMembers of the vascular endothelial growth factor (VEGF) and angiopoietin families regulate both angiogenesis and lymphangiogenesis by acting on vascular endothelial cells. [1][2][3][4] Angiopoietins (Ang1 and Ang2) bind to the Tie2 receptor tyrosine kinase, expressed almost exclusively on the surface of endothelial cells, and regulate interactions between endothelial and periendothelial cells. Ang1 is an obligate agonist of Tie2, whereas Ang2 can act as either an agonist or an antagonist, depending on the cell type and the surrounding microenvironment. [5][6][7] Ang1 expression in the mouse embryo occurs first in the myocardium and later in a more widespread manner around the developing vessels. 5 Ang2 is expressed in the embryonic dorsal aorta and the major aortic branches and in adults in tissues that are undergoing vascular remodeling. 6,8 Gene-targeting experiments have indicated that Ang1 is necessary for maintaining maximal interactions between endothelial cells, periendothelial cells, and the extracellular matrix. 9 In adult tissues, exogenous Ang1 prevents leakage of plasma components into the interstitium caused by powerful vascular permeability agents, such as VEGF. 10 Furthermore, abundant evidence suggests that members of the angiopoietin and VEGF families collaborate during different stages of angiogenesis. Ang2 is expressed at sites of pericyte detachment and blood vessel remodeling in conjunction with VEGF, whereas in the absence of VEGF, Ang2 activity leads to endothelial cell apoptosis. 6,11,12 In addition, factors that induce angiogenesis in vivo, such as hypoxia and VEGF, have been shown to up-regulate Ang2 in endothelial cells. 13 The role of angiopoietins in lymphangiogenesis has remained unclear although Tie2 mRNA and protein have been detected at least in cultured lymphatic endothelial cells. 14,15 Ang2 knockout mice have lymphatic defects, suggesting that Ang2 is needed for normal lymph vessel formation and stabilization. 8 Replacement of the Ang2 gene with a cDNA encoding Ang1 was sufficient to rescue the lymphatic phenotype but not the blood vascular phenotype. 8 Thus, it is possible that both Ang2 and Ang1 act as agonists of Tie2 in ...

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).…”

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.…”

Lymphangiogenesis in colorectal cancer—Prognostic and therapeutic aspects

“…Ang-1 has been demonstrated to promote lymphatic vessel sprouting, hyperplasia and growth in experimental animal models. 24,84 Ang-2 has not yet shown to directly induce lymphangiogenesis, and has probably a function as a lymphatic maturation factor. 87 Recently, 2 experimental studies have also identified Hepatocyte Growth Factor (HGF) as a lymphangiogenic factor.…”

“…In the normal colon and rectum, lymphatic vessels are located longitudinally beneath the muscularis mucosa with a few ascending branches reaching to the basal areas of the crypts and perpendicular branches reaching out deep into the submucosa. 22 Selective hyperplasia of the lymphatic vasculature as a result of growth factor (VEGF-C and Angiopoietin-1) overexpression in animal models has been demonstrated, 23,24 but at present little is known about possible structural and functional differences between normal and tumor-induced lymphatic vasculature.…”