Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice

Abstract

Molecular mechanisms regulating the remodeling of the lymphatic vasculature from an immature plexus of vessels to a hierarchal network of initial and collecting lymphatics are not well understood. One gene thought to be important for this process is Angiopoietin-2 (Ang-2). Ang2(-/-) mice have previously been reported to exhibit an abnormal lymphatic phenotype but the precise nature of the lymphatic defects and the underlying mechanisms have yet to be defined. Here we demonstrate by whole-mount immunofluorescence staining of ear skin and mesentery that lymphatic vessels in Ang2(-/-) mice fail to mature and do not exhibit a collecting vessel phenotype. Furthermore, dermal lymphatic vessels in Ang2(-/-) pups prematurely recruit smooth muscle cells and do not undergo proper postnatal remodeling. In contrast, Ang2 knock-out Ang1 knock-in mice do develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. Taken together, this work pinpoints a specific lymphatic defect of Ang2(-/-) mice and further defines the sequential steps in lymphatic vessel remodeling.

Claudin-like protein 24 interacts with the VEGFR-2 and VEGFR-3 pathways and regulates lymphatic vessel development

“…This suggests that, in mice, CLP24 may act during the later stages of lymphatic differentiation, when the SMC-covered collecting lymph vessels are demarcated from lymph capillaries (Tammela and Alitalo 2010). More SMC-covered enlarged lymphatic vessels have also been described in mice deficient of the Foxc2 transcription factor or angiopoietin-2, or having a mutant ephrinB2 Makinen et al 2005;Dellinger et al 2008). Although clp24 knockdown caused mild blood vascular defects in zebrafish and frog embryos, such were not found in the Clp24 À/À mice.…”

Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature

“…Mice hypomorphic for Tie1 exhibit dilated and disorganised lymphatic vessels with impaired lymphatic drainage capacity (D'Amico et al, 2010;Qu et al, 2010) and mice deficient in the gene encoding the TIE2 (TEK -Mouse Genome Informatics) ligand, Angpt2, display abnormal lymphatic vessel architecture, aberrant remodelling of the initial superficial capillary plexus and a failure of luminal valve formation (Gale et al, 2002;Dellinger et al, 2008).…”

A Human Monoclonal Anti-ANG2 Antibody Leads to Broad Antitumor Activity in Combination with VEGF Inhibitors and Chemotherapy Agents in Preclinical Models

“…Deletion of Ang2 in mice results in postnatal lethality and terminal vascular defects associated with poor blood vessel and lymphatic integrity and associated edema (16,17). Recently, anti-Ang2 antibodies, peptide-Fc fragments, and Ang2-specific RNA aptamers have shown in vivo efficacy and antiangiogenic activity in tumor models (18)(19)(20).…”