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14: The role of estrogen receptor-β (ESR2) on fetoplacental vascular function

      Objective

      Adequate fetoplacental blood flow is required for optimal fetal growth, and these vessels appear to be reduced in caliber in growth-restricted pregnancies. Regulation of fetoplacental vascular function is likely mediated by endothelial cell-derived vasoactive mediators, as these vessels lack innervation. Estrogen and its receptors, estrogen receptor-α and estrogen receptor-β (ESR2), promote overall vascular health by producing various vasodilators. Our prior data has demonstrated that of the estrogen receptors, placental villous endothelial cells solely express ESR2. Thus, we sought to determine the role of ESR2 in mediating fetoplacental vascular function

      Study Design

      Immunohistochemisty was performed on placental sections from growth-restricted pregnancies and gestational age-matched controls. Placental villous endothelial cells were isolated and cultured from term, uncomplicated pregnancies and treated with vehicle, estradiol, or diarylpropionitrile (DPN), an ESR2-specific agonist. RNA interference was utilized to knock-down ESR2. Real-time PCR and western blotting were performed, and cell culture supernatant were analyzed for prostanoid production via enzyme immunoassay.

      Results

      Immunohistochemistry demonstrated increased ESR2 expression within villous endothelial cells of growth-restricted pregnancies. Within cultured primary villous endothelial cells from uncomplicated pregnancies, neither estradiol nor DPN affected cyclooxygenase-2 (COX-2) or prostanoid levels. RNA interference of ESR2 led to a concomitant decrease in COX-2 mRNA (p<0.05) and protein levels, which was associated with diminished thromboxane levels (p≤0.003).

      Conclusion

      ESR2 expression patterns influence COX-2 and prostanoid levels within placental villous endothelial cells. Our data suggest that ESR2 may act via a ligand-independent mechanism to promote thromboxane production. Thus, elevated ESR2 expression within endothelial cells of growth-restricted pregnancies may be a key pathologic event, leading to increased COX-2 activity, thromboxane production, and vasoconstriction.