Mediators of impaired fetoplacental angiogenesis in fetal growth restriction

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Fetal growth restriction (FGR) is the second-leading cause of perinatal morbidity and mortality. Severe cases are oftentimes also complicated by abnormally high placental vascular resistance, as reflected clinically by abnormal umbilical artery Doppler indices on ultrasound. It is these fetuses with impaired blood flow on ultrasound that are at highest risk for stillbirth/death, neurodevelopmental delay, and/or long-term health problems. Currently, no preventative or therapeutic measures exist other than delivery, and clinical data show that this intervention still does not impact overall survival or long-term outcome. One major placental abnormality that is consistently seen in these severe cases of FGR is inadequate development of blood vessels within the placenta. These placentas have abnormally thin and malformed blood vessels, which leads to the poor blood flow within the fetus and placenta that can be seen on ultrasound. Our laboratory's long-term goal is to understand the cellular and molecular defects that occur in pregnancies complicated by severe fetal growth restriction. Currently, we know that cells lining the blood vessels of placentas - endothelial cells (ECs) - have molecular aberrations that cause them to migrate abnormally, which is one major cause of inadequate blood vessel formation. However, it is clear that in other organs, the non-cellular, proteinaceous tissue that surrounds ECs - the extracellular matrix (ECM) - can regulate EC cellular properties to promote and inhibit blood vessel formation. We have strong preliminary data showing that aberrant EC-ECM interactions in the human placenta result in impaired EC proliferation and migration. Thus, the main objective of this proposal is to determine the role of placental-specific EC-ECM interactions in the growth of placental blood vessels in these pregnancies complicated by severe FGR. To achieve this goal, we propose: [1] To identify abnormalities of EC-to-ECM (inside-out) signaling underlying impaired EC proliferation and migration, [2] To identify abnormalities of ECM-to-EC (outside-in) signaling underlying impaired EC proliferation and migration, and [3] To determine specific pathways regulated by faulty bi-directional signaling between ECs and ECM from severe FGR. Completion of the proposed aims will not only establish the individual roles of EC and ECM in EC-ECM signaling but will also identify key pathways of angiogenesis that are aberrantly regulated in placentas from severe FGR. This experimental model will generate new and clinically relevant data, setting a foundation for future studies investigating whether these abnormal molecular and cellular events can be targeted and "rescued." While fetal therapy for this often devastating complication is not on the immediate horizon, our experiments will provide key insights regarding potential targets for improving fetoplacental blood flow in pregnancies complicated by severe FGR.