Abstract 658: Beta-Catenin C-terminal Signaling Suppresses p53 in Vascular Smooth Muscle Cells and is Essential for Arteriogenesis
Arteriogenesis requires smooth muscle cell (SMC) investment of endothelial tubes to build the arterial wall. In preliminary studies in mice, inactivation of SMC β-catenin, a downstream mediator of canonical Wnt signaling and a key element of the structural cadherin-catenin complex, caused embryonic demise with apparent vascular enlargement and hemorrhage. In detailed analysis, we found that SMC β-catenin is required for arteriogenesis: embryos lacking SMC β-catenin (SMKO) died by E12.5 (93 embryos and 215 pups analyzed) with impaired arterial maturation, with thinner aortic walls by E10.5 (SMKO vs. WT p<0.0001, n=8) due to impaired SMC investment, decreased cell proliferation (E9.5 to E11.5 SMKO vs. WT p5), and increased apoptosis (E11.5 SMKO n=11 vs. WT n=18, p<0.05). Interestingly, β-catenin-deficient SMCs had impaired growth and survival and increased p53 activity, though p53 levels were unchanged. In vivo, SMC p53 inactivation suppressed phenotypes caused by loss of β-catenin: at E12.5, no β-catenin SMKOs looked normal, with 21% and 79% in early and advanced resorption, respectively; in contrast, 23% of p53/β-catenin double SMKOs looked normal, with 36% and 41% in early and advanced resorption, respectively (β-catenin SMKO n=29 vs. double SMKO n=22, p<0.01). Double SMKOs showed marked recovery of arterial wall formation. Mechanistically, signals from β-catenin’s C-terminal, but not N-terminal, interaction domain repressed p53 transcriptional activity in cultured SMCs (p<0.01, n=3). In vivo, studies of three different β-catenin knockin mutants showed that β-catenin signaling was required in SMCs, while structural function was not sufficient for arteriogenesis, as a structurally-competent but signaling-inert mutant β-catenin (n=11) phenocopied the SMKO (n=29). Moreover, signals from the C-terminal interaction domain were both required and generally sufficient for arteriogenesis: expression of a C-terminus β-catenin mutant in SMCs caused embryonic lethality (83 pups analyzed), while an N-terminus mutant permitted normal development (101 pups analyzed). Thus, SMC β-catenin-mediated repression of p53 is required for arteriogenesis, and its C-terminal interaction domain is important for this novel developmental role.
Author Disclosures: D.F. Riascos Bernal: None. P. Chinnasamy: None. T. Valenta: None. K. Basler: None. N.E.S. Sibinga: None.
This research has received full or partial funding support from the American Heart Association.
- © 2015 by American Heart Association, Inc.