Changing expression of cyclooxygenases and prostaglandin receptor EP4 during development of the human ductus arteriosus.

Programmed proliferative degeneration of the human fetal ductus arteriosus (DA) in preparation for its definite postnatal closure has a large developmental variability and is controlled by several signaling pathways, most prominently by prostaglandin (PG) metabolism. Numerous studies in various mammalian species have shown interspecies and developmental differences in ductal protein expression of cyclooxygenase (COX) isoforms and PG E receptor subtypes (EP1-4). We examined COX1, COX2, and EP4 receptor protein expression immunohistochemically in 57 human fetal autopsy DA specimens of 11-38 wk of gestation. According to their histologic maturity, specimens were classified into four stages using a newly designed maturity score that showed that histologic maturity of the DA was not closely related to gestational age. COX1 expression was found in all DA regions and rose steadily during development. COX2 staining remained weak throughout gestation. EP4 receptor staining increased moderately during gestation and was limited to the intima and media. In conclusion, histologic maturity classification helps to address developmentally regulated processes in the fetal DA. Concerning prostaglandin metabolism our findings are in line with animal studies, which assigned COX1 the predominant role in the DA throughout gestation. EP4 receptor presumably plays a key role for active patency of the human DA in the third trimester.