Iptakalim improves cerebral microcirculation in mice after ischemic stroke by inhibiting pericyte contraction

Abstract

Pericytes are present tight around the intervals of capillaries, play an essential role in stabilizing the blood–brain barrier, regulating blood flow and immunomodulation, and persistent contraction of pericytes eventually leads to impaired blood flow and poor clinical outcomes in ischemic stroke. We previously show that iptakalim, an ATP-sensitive potassium (K-ATP) channel opener, exerts protective effects in neurons, and glia against ischemia-induced injury. In this study we investigated the impacts of iptakalim on pericytes contraction in stroke. Mice were subjected to cerebral artery occlusion (MCAO), then administered iptakalim (10 mg/kg, ip). We showed that iptakalim administration significantly promoted recovery of cerebral blood flow after cerebral ischemia and reperfusion. Furthermore, we found that iptakalim significantly inhibited pericytes contraction, decreased the number of obstructed capillaries, and improved cerebral microcirculation. Using a collagen gel contraction assay, we demonstrated that cultured pericytes subjected to oxygen-glucose deprivation (OGD) consistently contracted from 3 h till 24 h during reoxygenation, whereas iptakalim treatment (10 μM) notably restrained pericyte contraction from 6 h during reoxygenation. We further showed that iptakalim treatment promoted K-ATP channel opening via suppressing SUR2/EPAC1 complex formation. Consequently, it reduced calcium influx and ET-1 release. Taken together, our results demonstrate that iptakalim, targeted K-ATP channels, can improve microvascular disturbance by inhibiting pericyte contraction after ischemic stroke. Our work reveals that iptakalim might be developed as a promising pericyte regulator for treatment of stroke.