Role of 15-lipoxygenase in Enhanced Pulmonary Vasoconstriction in Females

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DESCRIPTION (provided by applicant): Pulmonary arterial hypertension encompasses a group of diseases characterized by high pulmonary artery pressure and pulmonary vascular resistance. Vasoconstriction, vascular remodeling and thrombosis all contribute to the increased vascular resistance. Central to the proposed studies is that while relatively rare, idiopathic pulmonary arterial hypertension is a medically significant disease that occurs more frequently in young women. The disease is usually catastrophic for those afflicted. Mechanisms to explain the sex- difference in pulmonary arterial hypertension have not been well studied. The main focus of the current proposal is to use a rabbit model to explore the role of sex in a novel signaling pathway that regulates pulmonary vascular tone. Results will lay the fundamental conceptual groundwork for future studies to understand more completely the pathogenesis of pulmonary hypertension in women. Furthermore, this work is intended to advance new concepts in women's health research and the study of sex/gender differences. Specifically, our research provided the first evidence that in pulmonary arteries obtained from female rabbits, endothelium-dependent contractions to both arachidonic acid and methacholine were enhanced when compared to responses in males. Pharmacological studies with inhibitors of arachidonic acid metabolism indicated that the factor was a lipoxygenase metabolite. We also present the first data that lipoxygenase metabolites are increased in females compared to males and the protein expression of 15-lipoxygenase is greater in female pulmonary arteries. While sex differences in vascular responses to various vasoactive agents have been documented, no studies have investigated the role of sex differences on lipoxygenase metabolism of AA in pulmonary arteries. This proposal is designed to explore the specific hypothesis that differences in AA metabolism by 15-LO contribute to the increased endothelium-dependent pulmonary vasoconstriction in females compared to males. To further develop this novel hypothesis, studies will be performed in pulmonary artery vascular preparations using chemical, biochemical, physiological and pharmacological approaches. Two specific aims will be explored: 1) To chemically identify and biologically characterize the vasoconstrictor 15- lipoxygenase metabolite(s) produced by the rabbit pulmonary artery endothelium and 2) To examine the cellular mechanisms contributing to enhanced 15-lipoxygenase expression in females compared to males. These proposed studies will not only provide new insights into the role of endogenous arachidonic acid-derived factors in the pathogenesis of pulmonary arterial hypertension but will also advance our knowledge in women's health research by identifying possible mechanisms that contribute to sex-related differences in the incidence of pulmonary arterial hypertension. PUBLIC HEALTH RELEVANCE: While relatively rare, idiopathic pulmonary arterial hypertension is a medically significant disease that occurs more frequently in young women. The disease is usually catastrophic for those afflicted. Identifying endogenous pulmonary factors that may predispose females to the development of pulmonary hypertension is timely and important considering the abundance of clinical data indicating sex differences in vascular disease. Furthermore, this work is intended to advance new concepts in women's health research and the study of sex/gender differences.