Role of Smooth Muscle beta-catenin in Arterial Wall Formation and Vascular Remodeling after Injury

Abstract

Developmental arteriogenesis and adult vascular remodeling require smooth muscle cells (SMCs). Although beta-catenin provides essential structural and signaling functions during development and adult homeostasis, its contributions to in vivo SMC activities in vascular assembly and remodeling have not been characterized. We hypothesized that beta-catenin is an essential modulator of vascular SMC biology in vivo. We found that complete loss of beta-catenin in SMCs in the mouse decreased their proliferation and survival, limited arterial wall formation, and caused embryonic lethality. Interestingly, beta-catenin inhibited p53 transcriptional activity in SMCs in culture and in vivo, as concurrent loss of p53 improved arterial morphogenesis and embryonic development. Therefore, beta-catenin serves as an essential repressor of p53 in SMCs during arterial wall formation in the systemic circulation. Using a series of beta-catenin knock-in mutant alleles, we found further that SMC beta-catenin signaling function was essential, while its structural role was not sufficient. Specifically, the beta-catenin C-terminal interaction domain was required and sufficient to provide the necessary signal for arteriogenesis, whereas the N-terminal interaction domain was dispensable. This contributes to understanding how a vessel wall forms, which has implications for therapeutic and tumor angiogenesis, tissue engineering, and vascular disease. To characterize SMC beta-catenin function in adulthood, we employed a tamoxifen-inducible SMC-specific beta-catenin knockout strategy. We found that beta-catenin expression was undetectable in SMCs of normal arteries. In these vessels, beta-catenin function was dispensable to maintain their structure and state of SMC differentiation. However, upon arterial ligation, beta-catenin expression was induced; and in this context, loss of beta-catenin in SMCs significantly reduced cell proliferation and survival in the neointima and limited neointimal growth. Moreover, loss of beta-catenin in vascular SMCs decreased the expression of a set of pro-migration/invasion genes. Altogether, our developmental and adult mouse studies show that beta-catenin signaling function, especially that mediated by its C-terminal domain, promotes proliferation and survival of vascular SMCs in vivo, in part by repressing p53 activity in these cells. Thus, disrupting beta-catenin C-terminal interactions is an interesting potential therapeutic strategy for cardiovascular diseases associated with intimal hyperplasia such as atherosclerosis and restenosis.