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.
Wnt/beta-catenin is a molecular pathway that functions to control organ development and cell growth. Mutations in genes involved in the pathway have been linked to excessive growth in various cancers; because of this, there is substantial interest in developing new drugs to control the the activity of the pathway. Our studies to date suggest that the Wnt/beta-catenin pathway is also critical for vascular development and may contribute to vascular diseases such as restenosis and atherosclerosis. The work we propose here will advance knowledge of how the Wnt/beta-catenin pathway affects blood vessels, and assess whether drugs that control its activity may also be useful in vascular disease.
| Riascos-Bernal, Dario F; Sibinga, Nicholas E S; Kitsis, Richard N (2018) PDCD5 says no to NO. Proc Natl Acad Sci U S A 115:4535-4537 |
| Riascos-Bernal, Dario F; Chinnasamy, Prameladevi; Gross, Jordana N et al. (2017) Inhibition of Smooth Muscle ?-Catenin Hinders Neointima Formation After Vascular Injury. Arterioscler Thromb Vasc Biol 37:879-888 |
