Corticotrophin-releasing factor participates in S1PR3-dependent cPLA2 expression and cell motility in vascular smooth muscle cells.

This work is to investigate the role of CRF receptors in VSMC migration and the relevant mechanisms. We studied the role of CRF receptors in cell motility and found that S1P signaling pathway is involved in the regulation of cPLA2 induced by CRF. S1P is synthesized by Sphk1 and Sphk2 and binds to five GPCR designated S1P1-5. We observed that activation of CRFR1 resulted in increased cell migration, whereas activation of CRFR2 resulted in decreased cell migration. cPLA2 and iPLA2 were knocked down respectively to explore the corresponding effect on cell migration by means of shRNA interference. cPLA2 expression was increased by CRFR1 but decreased by CRFR2. On the contrary, iPLA2 expression was inhibited by CRFR1 but enhanced by CRFR2. The regulation of cPLA2 was in line with the regulation of Sphk1 and hence cell migration after the activation of CRFR1 or CRFR2. Consistently, S1P release was enhanced with CRFR1 activation. Both DMS (Sphk inhibitor) and CAY10444 (S1PR3 inhibitor) attenuated cPLA2 expression and thus decreased cell migration in response to CRF. In addition, CRF could not promote cell migration after S1PR3 silencing. Our results suggest the pro-migratory role of CRFR1-Sphk1-S1P-S1PR3-cPLA2 signaling pathway in VSMCs.