Perivascular Adipose Tissue–Derived Complement 3 Is Required for Adventitial Fibroblast Functions and Adventitial Remodeling in Deoxycorticosterone Acetate–Salt Hypertensive Rats

Objective— To examine the role of perivascular adipose tissue (PVAT)–derived factors in the regulation of adventitial fibroblast (AF) function in vitro and in vivo.Methods and Results— PVAT is an active component of blood vessels. Bioactive substances released from PVAT play regulatory roles in vascular function. However, their effects on vascular AFs remain unclear. PVAT-conditioned medium stimulated AF migration using a transwell technique, and differentiation was evaluated by α-smooth muscle–actin induction. We identified the secretome of PVAT by liquid chromatography–tandem mass spectrometry. One of the major secretory proteins in PVAT is complement 3 (C3). The C3 antagonist and neutralizing antibody attenuated PVAT-conditioned medium–induced AF migration and differentiation. Similar to PVAT-conditioned medium, C3 recombinant protein stimulated AF migration and differentiation. We demonstrated that the effects of PVAT-derived C3 were mediated by the c-Jun N-terminal kinase pathway. Moreover, we found morphological changes in perivascular adipocytes and increased expression of C3 in PVAT that was tightly associated with adventitial thickening and myofibroblast clustering around PVAT in deoxycorticosterone acetate–salt hypertensive rats.Conclusion— PVAT-derived C3 stimulated AF migration and differentiation via the c-Jun N-terminal kinase pathway. PVAT-derived C3 may contribute to adventitial remodeling in a deoxycorticosterone acetate–salt hypertensive model.