PROJECT SUMMARY/ABSTRACT: Statins are cholesterol-lowering drugs that have been clinically used for more than 30 years for the prevention and treatment of atherosclerotic cardiovascular diseases including coronary artery disease and stroke. The conventional view is that the vascular effects of statins are cholesterol lowering-dependent and/or -independent (or pleiotropic), both of which require long-term treatment. Surprisingly, studies to precisely determine direct vascular effects of statins are lacking and their clinical significance obscure, because almost all studies that reported vascular effects of statins were conducted a) using supratherapeutic concentrations (1000-fold or higher) of the drug, b) mostly on non-resistance, conduit arteries that do not control regional organ blood flow and systemic blood pressure, and c) on cultured arteries and smooth muscle cells that may have undergone transformation from a contractile to a non-contractile, proliferative phenotype. Our long-term goal is to understand direct arterial contractility regulation by therapeutic concentrations of statins on fresh isolated arteries and isolated myocytes. The rationale behind the proposed research is that the gained knowledge will be critical for enhancing our understanding of vascular actions of statins and future formulation of more effective, safer and personalized statin therapy. The objective of this application is to understand molecular mechanisms of direct statin effects on different vasculatures. Our novel preliminary data obtained using an integrated approach suggests that therapeutic concentrations (0.1-10nM) of statins produce both vasoconstriction and vasodilation depending on vascular microenvironment. Importantly, we found that such vascular effects occur at nanomolar concentrations, within 2-3 minutes of drug application and are independent of lipid synthesis inhibition by statins, suggesting cell-surface channel or receptor based mechanisms. Indeed, our data shows that statin-mediated vasoconstriction is dependent on smooth muscle cell L-type Ca2+ channel opening and Ca2+ influx, whereas vasorelaxation is consistent with cGMP-based phosphodiesterase (PDE) inhibition. The central hypothesis of this proposal is that statins have diverse vascular effects that are, at least, mediated by the activation of voltage-gated CaV1.2 ion channel and extracellular Ca2+ influx into arterial smooth muscle cells to cause vasocontraction, and inhibition of cGMP-dependent PDE in smooth muscle cells leading to vasodilation. The objective of the proposed research will be achieved using a combination of biochemical, molecular, imaging, genetic, in-vitro, in-silico and functional approaches. With a collaborative team of three prominent scientists, the proposed project will greatly enhance our understanding of novel vascular actions of the world’s most prescribed class of lipid-lowering medications. Our proposed activity will also establish infrastructure for cardiovas...