氧化三甲胺通过下调Mas受体诱导大鼠血管外膜成纤维细胞活化并促进病理性血管重构OA

AIM:To investigate whether trimethylamine N-oxide(TMAO)promotes pathological vascular re-modeling by regulating the activation of vascular adventitial fibroblasts through modulation of Mas receptor expression.METHODS:(1)For animal experiments,male Sprague-Dawley(SD)rats were randomly assigned to control,TMAO,TMAO+AVE0991(Mas receptor agonist),and TMAO+AVE0991+A779(Mas receptor inhibitor)groups,with 10 rats in each group.After 12 weeks of intervention,a common carotid artery balloon injury model was established,and samples were collected 2 weeks after surgery.Serum TMAO concentration was measured by high-performance liquid chromatogra-phy.Vascular morphology was evaluated by HE staining.The expression of vascular remodeling-and inflammation-related proteins was determined by immunohistochemistry,immunofluorescence,and Western blot.(2)For cell experiments,rat aortic adventitial fibroblasts were cultured and divided into control group and different drug treatment groups.Protein ex-pression was analyzed by Western blot and ELISA.Cell migration was assessed using Transwell and wound healing as-says.RESULTS:Animal experiments demonstrated that a high-choline diet successfully induced high TMAO levels in rats and exacerbated vascular remodeling following carotid artery injury.Compared with control group,the rats in TMAO group exhibited decreased Mas protein expression and increased expression of interleukin-6,α-smooth muscle actin,colla-gen type I,and matrix metalloproteinase 2.In TMAO+AVE0991 group,Mas protein expression was increased,whereas the expression of the other remodeling-related markers listed above was decreased.The addition of A779 attenuated the ef-fect of AVE0991.In vitro experiments further confirmed that both TMAO and the Mas receptor inhibitor A779 down-regu-lated Mas receptor expression,promoted phenotypic transformation of vascular adventitial fibroblasts,enhanced cell mi-gration,induced the secretion of inflammatory factors,and accelerated carotid artery vascular remodeling.These effects were effectively blocked by the Mas receptor agonist AVE0991.CONCLUSION:Treatment with TMAO down-regulates Mas receptor expression,and drives adventitial fibroblasts toward a pro-remodeling phenotype that exacerbates carotid ar-tery vascular remodeling.These findings suggest that Mas receptor may represent a key regulatory target in TMAO-associated vascular pathology.