β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke

Thrombin aggravates ischemic stroke and activated protein C (APC) has a neuroprotective effect. Both proteases interact with protease-activated receptor 1, which exhibits functional selectivity and leads to G-protein-and beta-arrestin-mediated-biased signal transduction. We focused on the effect of beta-arrestin in PAR-1-biased signaling on endothelial function after stroke or high-fat diet (HFD). Thrombin had a rapid disruptive effect on endothelial function, but APC had a slow protective effect. Paralleled by prolonged MAPK 42/44 signaling activation by APC via beta-arrestin-2, a lower cleavage rate of PAR-1 for APC than thrombin was quantitatively visualized by bioluminescence video imaging. HFD-fed mice showed lower beta-arrestin-2 levels and more severe ischemic injury. The expression of beta-arrestin-2 in capillaries and PDGF-beta secretion in HFD-fed mice were reduced in penumbra lesions. These results suggested that beta-arrestin-2-MAPK-PDGF-beta signaling enhanced protection of endothelial function and barrier integrity after stroke.