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Preeclampsia Is Associated with Impaired Regulation of the Placental Nitric Oxide-Cyclic Guanosine Monophosphate Pathway by Corticotropin-Releasing Hormone (CRH) and CRH-Related Peptides

Sir Quinton Hazell Molecular Medicine Research Centre (E.K., D.K.G.), Department of Biological Sciences, University of Warwick, Coventry CV4 7AL, United Kingdom; Division of Clinical Sciences (M.V., D.K.G.), Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom; and The Leeds Institute of Health, Genetics and Therapeutics (E.W.H.), University of Leeds, Leeds LS2 9NL, United Kingdom

Address all correspondence and requests for reprints to: Dr. D. K. Grammatopoulos, Sir Quinton Hazell Molecular Medicine Research Centre, Department of Biological Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom. E-mail: d.grammatopoulos{at}warwick.ac.uk.

During pregnancy, CRH and CRH-related peptides appear to regulate the fetoplacental circulation via activation of the nitric oxide (NO)/cGMP pathway. Pregnancies with abnormal placental function such as preeclampsia (PE) are characterized by increased maternal plasma CRH concentrations and reduced placental CRH-receptor 1 (CRH-R1) expression. In this study, we investigated the actions of CRH/CRH-related peptides on the NO/cGMP system in normal and PE placentas (n = 8 for each group).

Fluorescent in situ hybridization, RT-PCR, and immunofluorescence experiments in human term placenta detected mRNAs expression for both R1 and R2 types of CRH-R, as well as urocortin (UCN) II and UCN III and showed CRH-R protein expression mainly in syncytiotrophoblast, whereas the endothelial NO synthase (eNOS) expression was confined within the cytoplasm of the chorionic villi. In placental explants, CRH and UCN induced mRNA and protein expression of eNOS, but not inducible NOS, and also caused an acute increase in cGMP levels (maximal stimulation, 80–90% above basal; P < 0.05). UCN II also induced a modest induction of cGMP (42% above basal; P < 0.05). These responses were attenuated by the NOS and soluble guanylyl cyclase inhibitors, L-N^G-nitro-L-arginine methyl ester and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. In PE placental explants there was a significant reduction in CRH/CRH-related peptide-induced cGMP response; however, changes in the mRNA content of eNOS, inducible NOS, and soluble guanylyl cyclase (assessed by quantitative RT-PCR) between normal and PE placentas were not altered.

In conclusion, we demonstrated that CRH and CRH-related peptides can positively regulate the placental NO/cGMP system. This pathway appears to be impaired in PE and may contribute toward dysregulation of the balance controlling vascular resistance.

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