摘要Objectives: In this study, we explored how adiponectin mediated urotensin Ⅱ(UII)-induced tumor necrosis factor-α(TNF-α) and α-smooth muscle actin (α-SMA) expression and ensuing intracellular signaling pathways in adventitial fibroblasts (AFs). Methods: Growth-arrested AFs and rat tunica adventitia of vessels were incubated with UⅡ and inhibitors of signal transduction pathways for 1?24 h. The cells were then harvested for TNF-αreceptor (TNF-α-R) messenger RNA (mRNA) and TNF-α protein expression determination by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. Adiponectin and adiponectin receptor (adipoR) expression was measured by RT-PCR, quantitative real-time PCR (qPCR), immunohistochemical analysis, and cell counting kit-8 (CCK-8) cell proliferation experiments. We then quantified TNF-αandα-SMA mRNA and protein expression levels by qPCR and immunofluorescence (IF) staining. RNA interference (RNAi) was used to explore the function of the adipoR genes. To investigate the signaling pathway, we applied western blotting (WB) to examine phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). In vivo, an adiponectin (APN)-knockout (APN-KO) mouse model mimicking adventitial inflammation was generated to measure TNF-αandα-SMA expression by application of qPCR and IF, with the goal of gaining a comprehensive atlas of adiponectin in vascular remodeling. Results:In both cells and tissues, UⅡ promoted TNF-αprotein and TNF-α-R secretion in a dose-and time-dependent manner via Rho/protein kinase C (PKC) pathway. We detected marked expression of adipoR1, T-cadherin, and calreticulin as well as a moderate presence of adipoR2 in AFs, while no adiponectin was observed. Globular adiponectin (gAd) fostered the growth of AFs, and acted in concert with UⅡ to induceα-SMA and TNF-αthrough the adipoR1/T-cadherin/calreticulin/AMPK pathway. In AFs, gAd and UⅡ synergistically induced AMPK phosphorylation. In the adventitial inflammation model, APN deficiency up-regulated the expression ofα-SMA, UⅡ receptor (UT), and UⅡ while inhibiting TNF-αexpression. Conclusions:From the results of our study, we can speculate that UⅡ induces TNF-αprotein and TNF-α-R secretion in AFs and rat tunica adventitia of vessels via the Rho and PKC signal transduction pathways. Thus, it is plausible that adiponectin is a major player in adventitial progression and could serve as a novel therapeutic target for cardiovascular disease administration.