β‐catenin C‐terminal Domain/Sphingosine‐1‐Phosphate Receptor 1 Axis is a Potential Therapeutic Target in Vascular Remodeling

• DOI: 10.1096/fasebj.2022.36.s1.r5593
• Publication Date: 2022-05-03T08:40:44Z
• Authors: Gustavo H. Olivei...; Dippal Parikh; Gaia Ressa; Vanessa Almonte; Tomas Valenta; Konrad Basler; Dario Riascos‐Bernal; Nicholas Sibinga
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

Vascular smooth muscle cells (SMCs), in part via activation of the Wnt/β-catenin signaling pathway, contribute importantly to vascular remodeling. While C-terminal domain β-catenin links pathway gene expression, how this and related molecular mechanisms are involved remodeling is unknown. Inhibitors targeting specifically have been developed, but their use obstructive disease not yet justified because gap knowledge. Our group has previously shown that SMCs essential for arterial wall assembly during embryogenesis, its role adulthood Therefore, objective study was define importance underlying mechanisms. To test hypothesis required remodeling, mice bearing a mutant allele (ΔC) prevents transcription were crossed with SMC-specific SMA-CreERT2 line generate one flox knockin (Ctnnb1ΔC/flox ) or wt (Ctnnb1wt/flox allele. In system, tamoxifen administration removes allele, resulting (SMβCΔC mice) (SMβCwt/- as only sources SMCs. induce we performed carotid artery ligation week after injection male female adult mice. Carotid arteries from both SMβCΔC showed reduced neointima formation injury induced by compared SMβCwt/- Arteries also SMC proliferation increased apoptosis differentiation markers. We isolated mouse aortic (MASMCs) Ctnnb1ΔC/flox mice, transduced these GFP- Cre-expressing adenovirus obtain control (βCControl expressing β-cateninΔC (βCΔC found βCΔC MASMCs show growth βCControl . gain further insight on effects C-terminus, whole-transcriptome analysis RNA-seq downregulation sphingosine-1-phosphate receptor 1 (S1pr1) MASMCs. This known be important regulation fully elucidated. Interestingly, decreased S1PR1 expression injured SMβC∆C Consistent observation, mRNA protein levels S1pr1 promoter activity, which all rescued transfection constitutively active form β-catenin. By using S1PR1lox/stop/lox conditional gain-of-function line, overexpression rescues injury-induced Consistently, restored MASMC towards levels. Taken together, our results an domain-S1PR1 axis drives injury, identify multiple points potential therapeutic intervention disease.