CRH/CRHR1 modulates cerebrovascular endothelial cell permeability in association with S1PR2 and S1PR3 under oxidative stress

Abstract

Corticotrophin-releasing hormone (CRH) has been demonstrated to participate in vascular inflammation and permeability. Our previous studies have shown that blockade of S1PR2 or CRHR1 inhibited H2O2-induced brain endothelial hyperpermeability via inhibiting cPLA2 phosphorylation. However, little is known about the linkage between S1PRs and CRHR1 in oxidative stress-induced cerebrovascular endothelial hyperpermeability. Here we observed the opposite effects of S1PR2 to those of S1PR3 on the monolayer permeability of bEnd3 cells in response to H2O2. Interestingly, activation of CRHR1 was found to reverse the effects resulting from blockade/silencing of both S1PR2 and S1PR3. In bEnd3 monolayer, blockade/knockdown of S1PR2 reduced the endothelial hyperpermeability and suppressed the tight junction protein ZO-1 redistribution caused by H2O2, along with the inhibition of p38, ERK and cPLA2 phosphorylation. On the contrary, suppression/silencing of S1PR3 further promoted H2O2-induced endothelial hyperpermeability and ZO-1 redistribution, accompanied by the increased phosphorylation of p38, ERK and cPLA2. In the presence of CRH, the effects resulting from the suppression of both S1PR2 and S1PR3 were abolished. Our results elucidate a possible linkage between CRHR1 and S1PR2/S1PR3 involving in the regulation of endothelial monolayer permeability under oxidative stress condition.