This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Arsenic is an established, well-known vascular toxicant that is abundant in ground water and soil around areas with extractive industries. Exposure to arsenic through drinking water increases the frequency of miscarriage, stillbirth and spontaneous abortion in human populations. Our results from experimental mouse studies show that sodium arsenite (AsIII) exposure disrupts placental vasculogenesis, concomitant with placental dysplasia, causing spontaneous abortion between E7.5 and E12.5. Published reports indicate that stromal vascular endothelial growth factor (VEGF) ligand expression is upregulated by AsIII exposure, and our AsIII exposure data in cultured human microvascular endothelial cells (HMVECs) show increased VEGF receptor expression. Therefore, the central hypothesis states that arsenic toxicity causes placental dysplasia and disrupts VEGF-directed vasculogenesis resulting in placental insufficiency and spontaneous abortion.
The specific aims to test this hypothesis are (1) to identify the defect in placental morphogenesis caused by AsIII toxicity and (2) to conduct a functional analysis of the VEGF regulatory pathway to reveal the molecular mechanisms for how AsIII toxicity disrupts placental vasculogenesis. To accomplish these aims, we will utilize a mouse model to fate map stromal and endothelial cells during placentation, to measure key molecules in the VEGF regulatory pathway and to assess placental integrity and function. In addition, adeno-associated virus (AAV) transduction of HMVECs will be used to test the function of ligands, receptors and signaling components of the VEGF placental regulatory pathway. This project will provide a model for studying the morphogenic differences between angiogenesis and vasculogenesis, and most importantly, will offer insight into possible environmental causes of idiopathic human pregnancy complications.
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