Assistant ProfessorPhone: (601) 984-2320
Preeclampsia is a pregnancy specific disease that occurs in 5-10% of pregnancies worldwide. The disease is characterized as hypertension after the 20th week of pregnancy associated with new-onset proteinuria, endothelial dysfunction, systemic vasoconstriction, and an increased risk for cardiovascular disease later in life. A substantial amount of evidence suggests lack of spiral artery remodeling resulting in placental ischemia/hypoxia is the initiating event in the disease process. However, the factors contributing to the reduced vascular remodeling are unknown and a better understanding of placentation and the pathophysiology of the preeclamptic placenta is a compelling scientific pursuit and is the focus of this proposal. While the cyclooxygenase (COX) pathway has been the most extensively investigated, there are few studies on formation of cytochrome P450 (CYP450) metabolites of arachidonic acid (AA) and the significance for physiological and pathophysiological events in pregnancy. Furthermore, to date there are no studies addressing the role of CYP450 or AA in the remodeling of the maternal spiral arteries. One of the major metabolites of the CYP pathway, 20-hydroxyeicosatetraenoic acid (20-HETE), is reported to contribute to migration and proliferation of vascular smooth muscle cells in vitro and constrictive vascular remodeling in vivo. Within the rat placenta, CYP4A1 and 4A2 protein have been localized to the trophoblast layer. In humans, AA metabolism is reported to be altered within the preeclamptic placenta suggesting alterations in the balance of the metabolism of AA via the COX and CYP4A pathway could play an important role in the abnormal vascular remodeling and ischemia seen in preeclampsia. Furthermore, data suggests the Dahl S rat is a spontaneous model of pregnancy induced hypertension. Therefore, my research focuses around the central hypothesis that increases in CYP4A expression and production of 20-HETE in the placental vasculature, instead of normal upregulation of COX, leads to the abnormal spiral artery remodeling, reductions in placental perfusion, and triggers placental hypoxia/ischemia. Utilizing unique CYP4A transgenic and knockout rats on the Dahl S genetic background in addition to a translational element by profiling the metabolism of AA and the expression of COX and CYP4A enzymes in spiral arteries microdissected from the placenta of normal pregnant and preeclamptic women, we plan to test this hypothesis.
Through this research it is our goal to better understand how these factors are involved in the lack of vessel remodeling during preeclampsia. With this knowledge, new therapies geared toward increasing or decreasing these vessel factors can be developed. There are existing drugs that we can use to inhibit the formation of 20-HETE if our work proves that this is the factor causing abnormal vascular remodeling and preeclampsia. These therapies have potential to improve the outcomes of both mother and baby, in addition to the cardiovascular health of the mother later in life.
Current funding: AHA 14SDG20160020
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