Assistant Professor In-Residence
UCLA Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine
Congenital heart defects (CHDs) are the most common cause of congenital anomaly, occurring in ~1% of newborns. Among CHD types, single ventricle (SV) phenotypes have the worst clinical prognoses. These neonates generally survive in-utero; however, there is lifetime morbidity related to vascular sequalae -- protein losing enteropathy, hepatic fibrosis, and pulmonary arterio-venous malformations. Furthermore, there is a high incidence of mortality in infancy without cardiac transplantation or a series of staged surgical procedures. Despite making up only 5-8% of all CHD cases, SVs account for 25% of infant CHD deaths and only 50-70% survive beyond 5 years. The etiology(ies) remain elusive making intervention purely mechanical. Upstream and/or downstream signaling alterations in endothelial mechano-transduction throughout their life due to the abnormal flow patterns, remains a unifying phenotype. We have termed this the prenatal vascular phenotype.
To understand and target the mechanisms underlying the vascular phenotype, we aim to integrate data through the life course -- the prenatal and postnatal sequalae. We couple prenatal maternal-fetal imaging, underlying genetic predispositions, and developmental endothelial flow dynamics. By linking molecular data and environmental clues, mechanisms underlying SV pathology, and more specifically the prenatal vascular phenotype, will be uncovered. Ultimately, this may improve treatment that arise from loss of vascular integrity.
During pregnancy, the umbilical vessels provide a closed maternal-fetal circulatory system via the placenta to the fetus. A monolayer of endothelial cells (ECs) line the lumen of each vessel and translate the forces created by blood flow (35-250 milliliters per minute) into morphological and molecular responses that maintain homeostasis in each vessel of the maternal-fetal unit. Here, freshly isolated umbilical vein ECs, demarcated at the cell-junction by VE-Cadherin (red) and the actin cytoskeleton (green), show a response to fluid flow in vitro similar to that seen in vivo -- the cells elongate along the axis of flow, express Kruppel-Like Factor 2 (blue), and NOTCH1 (pink) polarizes downstream in the cells. Thus, each umbilical cord provides a model to identify the biomarkers responsible for the underlying etiologies of pregnancy-related maternal and fetal disease (i.e. preeclampsia, growth restriction, etc.) and is essential for developing precise mechanistic studies and effective therapeutics in pregnancy.
We have identified a population of patients with a clear unmet clinical need because of an underlying chronic dysfunction of hemodynamics related to endothelial cell dysfunction. Despite being born with a morbid CHD, we have a chance to understand downstream complications and interventions that can improve quality of life in these patients with lifelong sequelae related to an abnormal endothelial cell and vascular phenotype. Amongst non-genetic factors, alterations in hemodynamic forces alone have been shown to cause CHD in other species. A systematic mapping of hemodynamic forces in human CHD is yet to be performed and the potential role of altered flow as a predisposing factor in CHD has yet to be examined. More so, the downstream consequences of the vascular sequalae of CHD involve the same insult of endothelial cells (ECs) -- protein losing enteropathy, hepatic fibrosis, and pulmonary arterio-venous malformations. We focus on altered flow acting as a modifier in development and contributing to CHD. Flow is a well-defined mechanism and provides a platform to study physical forces that alter hemodynamics and of critical importance of gene expression in prenatally-diagnosed CHD with postnatal sequelae related to the vascular phenotype.
PRIORITY (Pregnancy CoRonavIrus Outcomes RegIsTrY), a nationwide registry of pregnant and postpartum women with or known or suspected COVID-19. Our team at UCLA has partnered with UCSF to establish this collaboration to answer critical questions for peripartum, neonatal, and postpartum patients with COVID-19 nationally and globally. Little is known about COVID-19 and its longstanding impact for women and babies. A robust research platform is needed to better understand the pathways of COVID-19 to identify risk factors and develop effective treatments. Our work includes maternal and neonatal outcomes and a biospecimen core to answer clinically relevant questions.
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Christine Jang, PharmD
Jenny Mei, MD
Ophelia Yin, MD