Vasoregulatory Function of CYP2E1-Derived Eicosanoids

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This is a proposal to investigate the role played by cytochrome P450 2E1 (CYP2E1 )-deriyed eicosanoids in the regulation of vasoconstrictor responsiveness and blood pressure in rats and mice. The proposal focuses on CYP2E1-dependent vascular production of 19(R)- and 18(R)- hydroxyeicosatetraenoic acids (HETE), the vasoregulatory action of such eicosanoids and their interaction with 20-HETE, and the notion that 19(R)- and 18(R)-HETE subserve antihypertensive functions by interfering with 20-HETE-induced sensitization of vascular smooth muscle to constrictor stimuli. The following aims will be addressed. AIM 1: To test the hypothesis that high blood pressure elicits reduction of vascular CYP2E1 and synthesis of 19(R)- and 18(R)-HETE, with attendant amplification of 20-HETE-induced sensitization to constrictor stimuli bringing about augmentation of vascular reactivity. Studies will be conducted in SHR, in rats made hypertensive by treatment with deoxycorticosterone or angiotensin II, and in normotensive controls. We seek to determine relationships between the level of blood pressure, vascular CYP2E1 expression and reactivity to constrictor stimuli as affected by 20-HETE and CYP2E1-derived eicosanoids. AIM 2: To test the hypothesis that gender, dietary potassium and dietary sodium influence vascular CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE, with consequential alterations in constrictor responsiveness resulting from changes in the effectiveness of the 20-HETE-dependent mechanism of vascular sensitization to constrictor stimuli. We will explore relationships between vascular CYP4A and CYP2E1 expression, synthesis of 20-, 19(R)- and 18(R)-HETE, and responsiveness to constrictor stimuli as a function of gender and dietary potassium and sodium. AIM 3: To test the hypothesis that upregulation of vascular CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE attenuates the development of hypertension. The effects of CYP2E1 gene transfer on blood pressure, vascular CYP2E1 and synthesis of CYP-derived eicosanoids, and reactivity of the vasculature to constrictor stimuli will be explored in SHR, and rats made hypertensive by angiotensin II infusion or injection of an adenoviral construct expressing CYP4A2. AIM 4: To test the hypothesis that reduction of vascular CYP2E1 activity and/or expression promotes elevation of blood pressure. We seek to determine whether blood pressure and blood pressure responsiveness to angiotensin II infusion are enhanced in rats undergoing inhibition of CYP2E1, and in CYP2E1-null mice.