Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

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DESCRIPTION (provided by applicant): Fetal growth restriction secondary to placental dysfunction is a major cause of perinatal morbidity and mortality. Specifically, abnormally elevated fetoplacental vascular resistance in these pregnancies (FGRadv), as reflected by abnormal umbilical artery Doppler velocimetry, is an ominous finding that substantially increases risk for adverse perinatal outcome, neurodevelopmental consequences, and long-term health problems. In contrast, growth-restricted pregnancies with preserved fetoplacental blood flow demonstrate perinatal outcomes similar to those with normal growth. This suggests that impaired blood flow within the fetoplacental circulation in FGR fetuses plays a major role in compromising fetal well-being and outcome. Currently, no preventive or therapeutic measures for FGRadv exist other than delivery, and clinical data demonstrate that this intervention does not impact overall survival or long-term outcome. Thus, understanding the mechanisms that result in FGRadv is crucial if we are to identify potential targets that can protect or restore fetoplacental blood flow and improve perinatal outcomes. One major placental abnormality that is consistently seen in FGRadv is a lack of adequate branching angiogenesis of the fetoplacental vasculature. In normal pregnancies, branching and non-branching angiogenesis persists throughout the second half of pregnancy, which allows for an appropriate decrement in placental vascular resistance that continues as gestation progresses. The overall objective of this proposal is to determine the molecular mechanisms by which improper fetoplacental angiogenesis occurs in FGRadv. We hypothesize that endothelium of FGRadv placentas result in impaired endothelial cell (EC) motility and EC-EC adherence. We further hypothesize that this is mediated by aryl hydrocarbon receptor nuclear translocator (ARNT; also known as hypoxia inducible factor 1-beta [HIF1?]), which results in down-regulation of vascular endothelial growth factor A (VEGFA) signaling. Our specific aims are as follows: (1) To characterize the functional endothelial cell-specific defect that impairs EC function and angiogenesis in FGRadv; (2) To determine the mechanism(s) by which ARNT regulates fetoplacental angiogenesis; (3) To establish the VEGFA signaling defects that impair proper EC function and fetoplacental angiogenesis. Completion of these aims will identify a major mechanistic pathway by which aberrant fetoplacental angiogenesis occurs and adversely impacts perinatal and long-term outcome of the fetus.