Endothelial cells (EC) release several factors that reduce vascular tone and counteract vasoconstriction including nitric oxide (NO) and prostaglandin (PG) I2. In the rabbit aorta and mouse mesenteric artery, endothelium-dependent relaxations to acetylcholine (ACh) are reduced, but not blocked, by inhibitors of NO and PG synthesis. These non-NO, non-PG-mediated relaxations are due to endothelium-dependent hyperpolarization of the smooth muscle cell (SMC) membrane and attributed to endothelium-derived hyperpolarizing factor. They are blocked by inhibitors of phospholipases, lipoxygenases (LOs) and potassium (K) channels. Arachidonic acid (AA) also causes endothelium-dependent relaxations and hyperpolarizations that are blocked by LO inhibitors, high extracellular K ([K]o) and apamin. Thus, the endothelium-dependent relaxations and hyperpolarizations to ACh and AA are mediated by a LO metabolite of AA. We have identified 2 endothelial vasodilator LO metabolites of AA: 11(R),12(S),15(S)-trihydroxy-eicosatrienoic acid (11,12,15-THETA) and 15-hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA). They relax and hyperpolarize SMCs through activation of an apamin-sensitive, small conductance, calcium-activated potassium (SKCa) channel. The proposed studies will test the hypothesis that AA is metabolized by the endothelium to vasodilator eicosanoids, including 11,12,15-THETA and 15-H-11,12-EETA, that regulate vascular tone, mediate the action of vasoactive hormones and regulate blood pressure. 1. We will characterize and regulate the major biosynthetic step involved in HEETA and THETA synthesis using wild type (WT), transgenic (TG) and/or knockout (KO) mice, antisense phosphorothiolated oligonucleotides (pOGNs) or short interfering RNAs (siRNAs) and pharmacological inhibitors. We will focus on endothelial 12/15-LO and 15-LO. We will determine the effect of these individual approaches on the synthesis of HEETA and THETA and vasorelaxation to ACh and AA. 2. We will investigate the mechanism of action of the HEETA and THETA using arteries of WT, TG and KO mice. We will use KO and TG mice to determine the role of the SMC SKCa subtype 2 channels in the hyperpolarizations and relaxations to HEETA, THETA, ACh and AA. 3. We will investigate the role of HEETA and THETA and SKCa channels in the regulation of vascular tone and blood pressure using WT, TG and/or KO mice. The specific mice and experimental conditions will be determined by the findings of aims 1 and 2. Blood pressure will be measured in anesthetized mice and the vasoconstrictor or vasodilator responses to agonists determined. Blood pressure will also be measured in WT, TG or KO mice made hypertensive with desoxycorticosterone acetate/1% sodium chloride (DOCA-salt), angiotensin II or a NO synthase inhibitor. These studies will test the hypothesis that endogenous LO metabolites are important regulators of vascular tone and blood pressure in mice.
The local regulation of the dilation and constriction of blood vessels is important in normal blood pressure control and contributes to pathological conditions as hypertension, diabetes and angina. These studies have defined a new class of vasodilators that are formed by the blood vessel wall. Knowledge of the role of these new endogenous vasodilators will help our understanding of the regulation of vascular tone and blood pressure.
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