Human placental development attaches the conceptus, through CTB invasion, to the uterus. Within the decidua CTBs intravasate uterine vessels, where they form heterotypic interactions with and soon replace the resident maternal cells. If formation of these unusual vascular connections is abrogated, serious complications, including intrauterine growth retardation and the syndrome preeclampsia (PE) can result. This laboratories recently published work shows that these unusual cell-cell interactions have equally unique molecular underpinnings. Invading CTBs switch their adhesion molecule repertoire to mimic that of the maternal vascular cells they replace. Since the CTBs continue to express differentiation markers that are unique to placental cells, we termed this process pseudovasculogenesis. This switch does not occur in PE, reinforcing its importance for normal pregnancy. Recent unpublished work shows that this transformation is more than """"""""skin deep,"""""""" as the cells also express VEGF/VEGF receptor, Ang/Tie, and ephrin family members that play critical roles in conventional vasculogenesis/angiogenesis. But CTB pseudovasculogenesis presents an interesting conundrum: the cells must execute this differentiation program without triggering angiogenesis in the maternal vessels they invade. The goal of the proposed experiments is to determine how CTBs accomplish this dual feat.
The aims are as follows:
(Aim 1) Finish characterizing ligands and receptors that are expressed as CTBs differentiate/ invade in vivo and in vitro. The goal is to understand which of the master regulators- VEGF/VEGF receptors, Ang/Tie and ephrin/ Eph- have expression patterns consistent with functional roles.
(Aim 2) Determine which receptor-ligand pairs regulate CTB pseudovasculogenesis. The hypothesis that VEGF and Ang family members regulate differentiation in the context of patterning, which is suspected of involving Eph and ephrin interactions.
(Aim 3) Assay the effects of CTB-derived factors on conventional angiogenesis. The hypothesis that CTBs render the uterine vessels they occupy incapable of mounting a conventional angiogenic response will be tested.
(Aim 4) Determine which regulators of CTB vasculogenesis and inhibitors of conventional angiogenesis are misexpressed in PE. The hypothesis that PE is associated with abnormal expression of vasculogenic/angiogenic factors at the maternal-fetal interface will be tested. At the conclusion of these experiments, great advances in our knowledge of the regulatory factors that enable CTBs to mimic endothelial cells during normal pregnancy and how this process changes in PE. The results could also have relevance outside the field of reproduction. For example, CTBs have developed novel strategies for the rendering the uterine vessels they invade quiescent. Whether these mechanisms could inhibit tumor-induced angiogenesis, and consequently tumor growth, is another intriguing possibility.
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