Freitas, I. N.; Lazaro, C. M.; da Silva Junior, J.; de Oliveira, K. M.; Victorio, J. A.; Carneiro, E. M.; Davel, A. P.

Background: Early-life protein restriction is a risk factor for cardiovascular disease, yet the mechanisms underlying vascular dysfunction and therapeutic strategies remain poorly defined. Tauroursodeoxycholic acid (TUDCA) is a bile acid that inhibits endoplasmic reticulum (ER) stress and has therapeutic potential in metabolic diseases. We hypothesized that TUDCA exerts vasculoprotective effects in the setting of post-weaning protein restriction. Methods: Post-weaning male and female mice fed a normoprotein (14% protein) or protein-restricted (6% protein, isocaloric) diet for 105 days. In the last 15 days, mice received TUDCA (300 mg/kg/day) or vehicle. Vascular function was assessed in the thoracic aorta with or without perivascular adipose tissue (PVAT). mRNA expression and histological analyses were performed in aorta and PVAT. Results: Long-term protein restriction resulted in endothelial dysfunction, vascular hypocontractility, and loss of the anticontractile effect of PVAT in males, but not females. These alterations were restored by TUDCA. In aorta, TUDCA normalized expression of eNOS and contractile phenotype-related genes -actin, SM22, Cav1.2 whereas, in the PVAT, TUDCA restored lipid content and expression of PRDM16, PPAR{gamma}, PGC1, leptin, and OB-Rb in protein-restricted mice. TUDCA attenuated fibrosis and ER stress markers while increased the bile acid receptor FXR expression in both tissues. Similar to TUDCA, ER stress inhibition with 4-phenylbutyric acid restored vascular and PVAT function in protein-restricted male mice. Conclusions: Post-weaning protein restriction induces vascular and PVAT dysfunction and fibrosis in males, associated with ER stress. TUDCA significantly attenuates these alterations, supporting its potential as a therapeutic strategy for vascular complications associated with early-life undernutrition.