Pregnancy induced resistance to UAE dysfunction

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): Pregnancy is a time of altered maternal vascular blood flow to divert blood to the uteroplacental unit. Dramataic increases in uterine artery (UA) vasodilation help maintain increased blood flow to the growing fetus. Preeclampsia is initially characterized by a failure to increase UA vasodilation, and is a leading causes of both maternal and perinatal morbidity and mortality. Recent studies suggest there is an increase in the subsequent risk of cardiovascular disease of mothers and their children. In women with preeclampsia, blood flow to other organs is reduced earlier than that to uterus, suggesting that uterine artery may be more resistant to injurious effect of preeclampsia in an attempt to maintain blood flow to the fetus. Preeclampsia is associated with increased maternal plasma levels of tumor necrosis factor alpha (TNF-a) and associated overproduce of ROS. ROS can acutely inactivate NO, but chronically can also induce mitochondrial dysfunction. We have developed a unique in vitro cell model that retains functional differences between UA endothelial cells (UAEC) from nonpregnant (NP) and pregnant (P) late term ewes, and developed methods to image [Ca2+]i, NO, and ROS in endothelium of intact uterine arteries ex vivo. In preliminary studies, we have shown that 1) the NO stimulant ATP induces initial Ca2+ oscillation followed by multiple Ca2+ burst in individual cells, and this response is greater in P-UAEC vs NP-UAEC; 2) TNF-a stimulates ROS production in NP-UAEC more than in P-UAEC; 3) chronic TNF-a exposure inhibits mitochondria function, and subsequently decreases ATP-induced [Ca2+]i, which can in turn be rescued by antioxidant. Our overall objective is (1) to determine the mechanisms of ROS generation in response to TNF-a and the underlying cause of pregnancy-specific resistance to TNF-a-induced UA endothelial dysfunction in our UAEC model in vitro, as well as means to rescue the cells from TNF-a-induced damage and (2) to extend these findings to the uterine artery itself ex vivo, so verifying the mechanism at work in vivo. In this way we hope to provide the basis for further in vivo studies to model dysfunctional aspects of preeclampsia in sheep as well as form the basis for future translational work into primates and humans.