p120-Catenin Is Required for Mouse Vascular Development

Abstract

Rationale p120-catenin (p120) is an armadillo family protein that binds to the cytoplasmic domain of classical cadherins and prevents cadherin endocytosis. The role of p120 in vascular development is unknown. Objective The purpose of this study is to examine the role of p120 in mammalian vascular development by generating a conditionally mutant mouse lacking endothelial p120 and determining the effects of the knockout on vasculogenesis, angiogenic remodeling, and the regulation of endothelial cadherin levels. Methods and Results A conditional Cre/loxP gene deletion strategy was used to ablate p120 expression, using the Tie2 promoter to drive endothelial Cre recombinase expression. Mice lacking endothelial p120 died embryonically beginning at E11.5. Major blood vessels appeared normal at E9.5. However, both embryonic and extraembryonic vasculature of mutant animals were disorganized and displayed decreased microvascular density by E11.5. Importantly, both vascular endothelial (VE)-cadherin and N-cadherin levels were significantly reduced in vessels lacking p120. This decrease in cadherin expression was accompanied by reduced pericyte recruitment and hemorrhaging. Furthermore, p120-null cultured endothelial cells exhibited proliferation defects that could be rescued by exogenous expression of VE-cadherin. Conclusions These findings reveal a fundamental role for p120 in regulating endothelial cadherin levels during vascular development, as well as microvascular patterning, vessel integrity, and endothelial cell proliferation. Loss of endothelial p120 results in lethality due to decreased microvascular density and hemorrhages.

Integrin β1 controls VE-cadherin localization and blood vessel stability

“…The interaction between VE-cadherin and p120 d-catenin prevents clathrin-dependent endocytosis of the cadherin and is essential for endothelial barrier function [26][27][28][29] . In control retinal vessels, anti-p120 immunosignal was visible at endothelial cell-cell contacts and overlapped with anti-VE-cadherin staining (Fig.…”

Classical and desmosomal cadherins at a glance

“…For example, mutations in regulators of membrane trafficking, such as Rab11, a member of the Ras superfamily of monomeric G-proteins, and dynamin, a GTPase responsible for endocytosis in eukaryotic cells, result in substantial alterations in cadherin distribution and phenotypes that can, at least in part, be explained by altered adhesion (Niessen et al, 2011). Furthermore, ablating p120-catenin gene (Ctnnd1) expression leads to decreased steady state cadherin levels in most tissues analyzed, presumably because of increased cadherin endocytosis and turnover Elia et al, 2006;Oas et al, 2010;Perez-Moreno et al, 2006). Type I gamma phosphatidylinositol-4-phosphate 5-kinase (PIPKIc) modulates Ecadherin trafficking by binding directly to Ecadherin and preventing the association of cadherin with the adaptor protein complex 1 (AP-1), a clathrin adaptor complex that is important for delivery of newly synthesized and recycled receptors to the plasma membrane.…”

p120-catenin is essential for terminal end bud function and mammary morphogenesis

“…These animals die from gastrointestinal bleeding within 3 weeks of birth. Other p120 KOassociated defects include reduced vessel density and anomalies in dendritic spine and synapse development in hippocampal neurons (Elia et al, 2006;Oas et al, 2010). Surprisingly, p120 KO in the prostate has no detectable effect on either cell morphology or adhesion despite near complete loss of E-cadherin expression (A.B.R., unpublished).…”

“…Phenotypes associated with p120 ablation in vivo appear to be largely tissue dependent and surprisingly unpredictable (Bartlett et al, 2010;Elia et al, 2006;Marciano et al, 2011;Oas et al, 2010;Perez-Moreno et al, 2006;SmalleyFreed et al, 2010;Stairs et al, 2011). For example, in the developing salivary gland, p120 ablation completely blocks acini formation .…”