Phosphatidylinositol 3‐kinase‐δ up‐regulates L‐type Ca2+ currents and increases vascular contractility in a mouse model of type 1 diabetes

BACKGROUND AND PURPOSE Vasculopathies represent the main cause of morbidity and mortality in diabetes. Vascular malfunctioning in diabetes is associated with abnormal vasoconstriction and Ca2+ handling by smooth muscle cells (SMC). Phosphatidylinositol 3‐kinases (PI3K) are key mediators of insulin action and have been shown to modulate the function of voltage‐dependent L‐type Ca2+ channels (CaV1.2). In the present work, we investigated the involvement of PI3K signalling in regulating Ca2+ current through CaV1.2 (ICa,L) and vascular dysfunction in a mouse model of type I diabetes. EXPERIMENTAL APPROACH Changes in isometric tension were recorded on myograph. Ca2+ currents in freshly dissociated mice aortic SMCs were measured using the whole‐cell patch‐clamp technique. Antisense techniques were used to knock‐down the PI3Kδ isoform. KEY RESULTS Contractile responses to phenylephrine and KCl were strongly enhanced in diabetic aorta independent of a functional endothelium. The magnitude of phenylephrine‐induced ICa,L was also greatly augmented. PI3Kδ expression, but not PI3Kα, PI3Kβ, PI3Kγ, was increased in diabetic aortas and treatment of vessels with a selective PI3Kδ inhibitor normalized ICa,L and contractile response of diabetic vessels. Moreover, knock‐down of PI3Kδin vivo decreased PI3Kδ expression and normalized ICa,L and contractile response of diabetic vessels ex vivo. CONCLUSIONS AND IMPLICATIONS Phosphatidylinositol 3‐kinase δ was essential to the increased vascular contractile response in our model of type I diabetes. PI3Kδ signalling was up‐regulated and most likely accounted for the increased ICa,L, leading to increased vascular contractility. Blockade of PI3Kδ may represent a novel therapeutic approach to treat vascular dysfunction in diabetic patients. LINKED ARTICLE This article is commented on by Sturek, pp. 1455–1457 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00997.x