PI3Kγ inhibition reduces blood pressure by a vasorelaxant Akt/L-type calcium channel mechanism

Aims The lipid and protein kinase phosphoinositide 3-kinase gamma (PI3K gamma) is abundantly expressed in inflammatory cells and in the cardiovascular tissue. In recent years, its role in inflammation and in cardiac function and remodelling has been unravelled, highlighting the beneficial effects of its pharmacological inhibition. Furthermore, a role for PI3K gamma in the regulation of vascular tone has been emphasized. However, the impact of this signalling in the control of blood pressure is still poorly understood. Our study investigated the effect of a selective inhibition of PI3K gamma, obtained by using two independent small molecules, on blood pressure. Moreover, we dissected the molecular mechanisms involved in control of contraction of resistance arteries by PI3K gamma. Methods and results We showed that inhibition of PI3K gamma reduced blood pressure in normotensive and hypertensive mice in a concentration-dependent fashion. This effect was dependent on enhanced vasodilatation, documented in vivo by decreased peripheral vascular resistance, and ex vivo by vasorelaxing effects on isolated resistance vessels. The vasorelaxation induced by PI3K gamma inhibition relied on blunted pressure-induced Akt phosphorylation and a myogenic contractile response. Molecular insights revealed that PI3K gamma inhibition affected smooth muscle L-type calcium channel current density and calcium influx by impairing plasma membrane translocation of the alpha 1C L-type calcium channel subunit responsible for channel open-state probability. Conclusion Overall our findings suggest that PI3K gamma inhibition could be a novel tool to modulate calcium influx in vascular smooth muscle cells, thus relaxing resistance arteries and lowering blood pressure.