Canonical Wnt/beta-catenin (?-ctn) signaling plays a crucial role in embryonic development and homeostasis of many adult tissues. Conditional inactivation of ?-ctn, the sole downstream mediator of pathway activity, demonstrates its necessity in multiple diverse processes in vivo. Inactivation of ?-ctn in endothelial cells (ECs), for example, yields embryonic vascular defects limited to the central nervous system, while systemic vascular development appears normal. Interestingly, our recent studies show that inactivation of ?-ctn in vascular smooth muscle cells (SMCs) in mice causes death by embryonic day (E) 12.5, with systemic arteries that are dilated and incompetent due to impaired SMC proliferation, survival, and investment of the developing vascular wall. Thus during development, SMCs of the systemic circulation require ?-ctn expression, while corresponding ECs do not. Our mechanistic analysis indicates that the former effect depends in part on critical signals from the ?-ctn C-terminal domain that suppress acetylation and activity of the tumor suppressor p53. ?-ctn functions in the adult vasculature and its potential roles in vascular homeostasis or remodeling are not well understood. Our preliminary studies indicate that SMC ?-ctn can be inactivated in the adult mouse without immediate vascular consequences, but that neointimal formation after vascular injury is significantly reduced by its absence. How ?-ctn inhibition affects adult vascular integrity, response to injury, and atherosclerosis has not been reported. These gaps in our understanding are significant, because aberrant ?-ctn signaling has been implicated in the pathogenesis of multiple cancers, and thus inhibition of ?-ctn serves as a potentially important target in several emerging anti-neoplastic strategies. This proposal encompasses three aims: first, to determine how ?-ctn suppresses SMC p53 activity, second, to assess ?-ctn structural and N- vs C-terminal signaling functions in vascular homeostasis, injury response, and atherosclerosis, and third, to test Wnt/?-ctn inhibition as a potential therapeutic strategy for control of accelerated vascular remodeling and/or atherosclerosis. Analysis of ?-ctn in vascular function is relevant to understanding how new therapies based on Wnt/?-ctn inhibition may affect vascular homeostasis, and should allow us to evaluate the safety of such approaches and their potential utility in treatment of vascular disease.
|Effective start/end date||6/15/17 → 2/28/18|
- National Heart, Lung, and Blood Institute: $653,470.00
- Molecular Medicine
- Cell Biology
- Developmental Biology