NIH grant: Wnt/Beta-catenin and vascular remodeling (1R01HL181566-01A1)

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NIH grant 1R01HL181566-01A1: Wnt/Beta-catenin and vascular remodeling
Institute: {'code': 'HL', 'abbreviation': 'NHLBI', 'name': 'National Heart Lung and Blood Institute', 'admin_org_id': '12500068', 'admin_funding_url': ''}. PI: Nicholas E Sibinga. Award: $1583381.
Start: 2026-08-15T00:00:00.
Wnt/beta-catenin and vascular remodeling
Vascular remodeling is essential for vertebrate development, but this process is also a hallmark
of important cardiovascular diseases, including atherosclerosis and restenosis after vascular
intervention. As such, it contributes importantly to myocardial infarction, stroke, and peripheral
artery disease. Canonical Wnt/beta-catenin (β-Ctn) signaling is essential for embryonic
development and homeostasis of many adult tissues. In previous studies, we found that β-Ctn in
SMCs is essential for arterial wall formation in development and for neointimal formation after
arterial injury in the mature vasculature. These findings are of translational interest, because
multiple pharmacologic tools that modify β-Ctn signaling have been developed, intended
primarily as potential therapies for β-Ctn-dependent cancers. Importantly, β-Ctn signaling is
modular, and strategies have targeted global, C-terminal-, or N-terminal-associated β-Ctn
signaling activities in order to identify the most selective but effective pharmacologic
intervention.
Our preliminary studies indicate that genetic inactivation of SMC β-Ctn C-terminal signaling in
the adult mouse with a normal vasculature is well tolerated, without effects on blood pressure or
arterial structure, for at least 3 months. Importantly, this same intervention decreases neointimal
formation after vascular injury. The β-Ctn N-terminus in SMCs is also important in development,
but its role in vascular injury response has not been evaluated. We hypothesize that discrete
pharmacologic targeting of β-Ctn signaling may have beneficial effects on vascular remodeling.
The overall goals of this project are to understand how β-Ctn signaling contributes to vascular
remodeling and diseases such as atherosclerosis and restenosis, and to identify the most
effective and safe way to modify β-Ctn signaling to ameliorate these pathogenetic processes.
Toward these ends, we propose 3 aims based on preclinical modeling of vascular disease in
mice, using cell culture, in vivo methods, and proteomic and phosphoproteomic strategies. First,
we will investigate in detail how signals from the β-Ctn N- and C-termini affect the macrophage
phenotype and vascular remodeling. Second, we will evaluate the function of N- or C-terminal
signals in SMCs. Finally, we will test if pharmacologic inhibitors of β-Ctn can reverse established
vascular disease and analyze components of the β-Ctn pathway in diseased human vascular
tissues.

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