Sex, Vascular Tone and Arachidonic Acid Metabolism
Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive increase in pulmonary vascular resistance that if untreated results in right ventricular failure and death. Despite major therapeutic advances in the last decade, there is no cure for this disease. Recent evidence showed that the female-to-male ratio in the incidence of PAH has increased from 1.7:1 in the 1980’s to 4.1:1 in 2007. This is an alarming statistic that needs to be addressed experimentally. Mechanisms to explain the female predominance are scarce but likely relate to changes in estrogen that contribute to the pathogenesis of the disease. While the human data predicts that estrogen contributes to disease progression, studies in many animal models reported that estrogen was protective and decreased the severity of PAH. Because of these inconsistencies, our laboratory developed a different experimental approach and showed in a rabbit model without any manipulations to elicit PAH that there are sex-based differences in pulmonary artery vasoconstriction attributable to 15-hydroxyeicosatrienoic acid (HETE). 15-HETE is a 15-lipoxygenase (LO) metabolite of the arachidonic acid pathway. Our data showed that females had increased expression of 15-LO, increased production of 15-HETE and increased sensitivity to 15-HETE-mediated vasoconstriction compared to males. Equally exciting were results that showed that estrogen treatment of male pulmonary arteries increased 15-LO expression and 15-HETE production. Specific studies are designed to define the mechanisms that explain the interaction of estrogen and 15-HETE and how these mechanisms contribute to female predominance in PAH. Experiments address the hypothesis that the increased pulmonary artery vasoconstriction in females compared to males is due to a unique combination of mechanisms: 1) estrogen modulation of 15-LO expression via activation of the cytokine signal transducer and activator of transcription pathway and 2) increased 15-HETE sensitivity due to increased inhibition of voltage-gated potassium channels and/or increased 15-HETE receptor expression. Identifying the described mechanisms will likely provide new insights into female predominance in PAH and lead to new options for treatments.
Thromboxane Receptors in Atherosclerosis
More than 90 million Americans have elevated blood cholesterol and an increased likelihood of developing atherosclerosis. The overall goal of our research is to explore novel mechanisms that contribute to atherosclerosis. Of particular interest to our laboratory is evidence that the synthesis of thromboxane, a metabolite of arachidonic acid in platelets, increases in atherosclerosis, and blockade of thromboxane receptors attenuates atherosclerotic plaque formation. The current therapeutic strategy of low dose aspirin to protect against cardiovascular disease provides further evidence that thromboxane is an important component of the vascular responses in atherosclerosis since this regimen is designed to selectively inhibit platelet thromboxane production. While it is well established that thromboxane promotes both platelet aggregation and vascular smooth muscle vasoconstriction, the exact role of vascular and platelet thromboxane receptor activation in the development and progression of atherosclerosis remains unclear. Our previous work identified a subgroup of rabbits deficient in vascular but not platelet thromboxane receptors. Our research examines the overall objective that the vascular thromboxane receptor plays a role in the pathogenesis of atherosclerosis that is distinct from the role of the platelet thromboxane receptor. The central hypothesis is that an absence of vascular thromboxane receptors delays the development and progression of atherosclerosis resulting in preserved endothelial function. Studies are designed 1) to evaluate the development and progression of atherosclerosis in rabbits with and without vascular thromboxane receptors, 2) to investigate the hypothesis that activation of endothelial thromboxane receptors contributes to the pathogenesis of atherosclerosis, and 3) to examine the role of the platelet thromboxane receptor in the pathogenesis of atherosclerosis. The further understanding of the role of vascular and platelet thromboxane receptors in the pathogenesis of atherosclerosis as outlined by this proposal will allow the development of future therapeutic treatments.
Pfister, SL, Nithipatikom, K, Campbell, WB: Role of superoxide and thromboxane receptors in acute angiotensin II-induced vasoconstriction of rabbit vessels. Amer. J. Physiol. Heart Circ. Physiol, 300(6): H2064-7, 2011.
Pfister, SL, Role of lipoxygenase metabolites of arachidonic acid in enhanced pulmonary artery contractions of female rabbits. Hypertension, 57:825-832, 2011.
Pfister, SL, Gauthier, KM, Campbell, WB: Vascular pharmacology of epoxyeicosatrienoic acids. In Advances in Pharmacology, PM Vanhoutte, Ed, Vol. 60:27-59, 2010.
Aggarwal, NT, Phister, SL, Gauthier KM, Chawengsub Y, Baker JE, Campbell WB: Chronic hypoxia enhances 15-lipoxygenase mediated vasorelaxation in rabbit arteries. Am J Physiol Heart Circ. Physiol. 296:H678-88, 2009.
Pfister, SL, Aortic thromboxane receptor deficiency alters vascular reactivity in cholesterol-fed rabbits. Atherosclerosis, 189:358-363, 2006.
Pfister, SL, Kotulock, DA, Campbell, WB: Vascular smooth muscle thromboxane A2 receptors mediated arachidonic acid-induced sudden death in rabbits. Hypertension 29:303-309,1997.