Angiopoietin-2 Is Required for Postnatal Angiogenesis and Lymphatic Patterning, and Only the Latter Role Is Rescued by Angiopoietin-1

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Developmental Cell (Impact Factor: 9.71). 10/2002; 3(3):411-23. DOI: 10.1016/S1534-5807(02)00217-4
Source: PubMed


VEGF and Angiopoietin-1 requisitely collaborate during blood vessel development. While Angiopoietin-1 obligately activates its Tie2 receptor, Angiopoietin-2 can activate Tie2 on some cells, while it blocks Tie2 activation on others. Our analysis of mice lacking Angiopoietin-2 reveals that Angiopoietin-2 is dispensable for embryonic vascular development but is requisite for subsequent angiogenic remodeling. Unexpectedly, mice lacking Angiopoietin-2 also exhibit major lymphatic vessel defects. Genetic rescue with Angiopoietin-1 corrects the lymphatic, but not the angiogenesis, defects, suggesting that Angiopoietin-2 acts as a Tie2 agonist in the former setting, but as an antagonist in the latter setting. Our studies define a vascular growth factor whose primary role is in postnatal angiogenic remodeling and also demonstrate that members of the VEGF and Angiopoietin families collaborate during development of the lymphatic vasculature.

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    • "Although Tie receptors were initially thought to be orphan receptors, extensive studies have identified four ligands that can bind to Tie receptors: angiopoietins 1–4, (Davis et al., 1996; Suri et al., 1996; Maisonpierre et al., 1997; Valenzuela et al., 1999). These ligands have also been shown to be necessary for the regulation of yolk sac vascular remodeling in the mouse embryo (Davis et al., 1996; Maisonpierre et al., 1997; Gale et al., 2002). These data identify the Tie family of receptors and ligands as critical molecular regulators of vascular remodeling during angiogenesis , after the initial establishment of the capillary plexus during vasculogenesis. "
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    ABSTRACT: Vascular remodeling of the mouse embryonic yolk sac is a highly dynamic process dependent on multiple genetic signaling pathways as well as biomechanical factors regulating proliferation, differentiation, migration, cell-cell, and cell-matrix interactions. During this early developmental window, the initial primitive vascular network of the yolk sac undergoes a dynamic remodeling process concurrent with the onset of blood flow, in which endothelial cells establish a branched, hierarchical structure of large vessels and smaller capillary beds. In this review, we will describe the molecular and biomechanical regulators which guide vascular remodeling in the mouse embryonic yolk sac, as well as live imaging methods for characterizing endothelial cell and hemodynamic function in cultured embryos.
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    • "ANG2 maintains the integrity of the collecting lymphatics during postnatal development We then examined whether ANG2 regulates LEC junctions in collecting lymphatics during postnatal development . Similar to constitutive Ang2 deletion (Gale et al. 2002; Dellinger et al. 2008), postnatal ANG2 inhibition with the blocking antibody also induced chylous ascites in nine out of 32 P5 pups (Supplemental Fig. S5A), and essentially all of the anti-ANG2-treated neonates showed chyle leakage into the mesentery (Fig. 6A–D). Furthermore , the LEC morphology in the collecting lymphatics became rounded, and the junctions were disrupted, with a jagged shape and breaks of zipper continuity (Fig. 6E–H). "
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    • "It is clear that disrupting cellular or genetic mechanisms that promote endothelial cell apoptosis can lead to persistence of the hyaloid vessels. Examples include loss of Wnt7b signals in macrophage-like hyalocytes [12], and the absence of Angiopoietin 2 [13,14] or p53 [15,16], which may be linked to endothelial cell apoptosis in the postnatal period [16]. HVS regression is also blocked by hyperplasia of perivascular cells in the primary vitreous. "
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