Vascular Physiology and Pharmacology of Cytochrome P450- and Catechol-O-Methyltransferase-Derived Metabolites of Estrogen on Uterine Endothelial Adaptations during Pregnancy

Accumulating experimental data provide convincing evidence that some metabolites of estrogen are biologically active and mediate multiple effects on the cardiovascular system. Estrogen is significantly elevated during pregnancy and some of the maternal vascular adaptations during pregnancy are mediated, in part, by estrogens via the classical estrogen receptors. However, it is largely unclear whether estrogen metabolites can modulate maternal vascular adaptations during. Therefore, we propose a thesis study designed to test the vascular physiology and pharmacology of estrogen metabolites on pregnancy vascular adaptation especially on endothelial-mediated angiogenic activity and vasodilator production. We hypothesize that estrogen-induced uterine endothelial vasodilatory and angiogenic responses during pregnancy are in part mediated via its biologically active metabolites, the catecholestradiols and the methoxyestradiols. Our results in these studies demonstrate that during pregnancy, plasma increases in estrogen levels are paralleled by distinct increases in the estrogen metabolites including the catecholestradiols and methoxyestradiols. In addition, we show herein that estrogen metabolites induce proliferation in uterine artery endothelial cells derived from the pregnant state but not from the nonpregnant state.;Estrogen metabolites also induced a higher increase in prostacyclin production by uterine artery endothelial cells derived from the pregnant state compared to the nonpregnant state. We also demonstrate that unlike the parent estrogen, estrogen metabolites-induced uterine endothelial vasodilatory and angiogenic responses during pregnancy are mediated independent of the classical estrogen receptors and occur via adrenergic or other unidentified endothelial receptors and are facilitated by mitogen-activated protein kinases. Clinically, our findings show that preeclampsia is characterized by aberrant synthesis, metabolism, and plasma accumulation of estrogens and estrogen metabolites that are likely to be associated with alterations in maternal pregnancy-induced vascular functions. Collectively, the studies in the thesis present strong evidence that during pregnancy estrogen-induced uterine endothelial vasodilatory and angiogenic responses involve its sequential metabolic conversion to catecholestradiols and methoxyestradiols which are capable of stimulating estrogen receptor-independent endothelial vasodilatory and angiogenic endothelial adaptations during pregnancy.