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Expression and Biological Activity of Parathyroid Hormone-Related Peptide in Pregnant Rat Uterine Artery: Any Role for 8-Iso-Prostaglandin F₂?

Université Louis Pasteur-Strasbourg I, Institut Gilbert-Laustriat and Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7175 (F.M., H.K., A.G.), Département Pharmacologie et Physicochimie, Faculté de Pharmacie, 67401 Illkirch, France; Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 771 (F.M., A.T., R.A.); CNRS UMR 6214; Faculté de Médecine, Université d’Angers, 49045 Angers, France; INSERM Unité 727 (S.W., M.B.), Université Louis Pasteur (Strasbourg I), 67070 Strasbourg, France; Département de Réanimation médicale et de médecine hyperbare (F.M.), Centre Hospitalier Universitaire, 49933 Angers, France; and Réanimation Médicale (H.K., F.S.), Hôpital de Hautepierre, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France

Address all correspondence and requests for reprints to: Pr. Alexis Gairard, Institut Gilbert-Laustriat, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7175, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch, France. E-mail: alexis.gairard{at}pharma.u-strasbg.fr.

PTHrP is produced in vessels and acts as a local modulator of tone. We recently reported that PTHrP(1–34) is able to induce vasorelaxation in rat uterine arteries, but in pregnancy, this response is blunted and becomes strictly endothelium dependent. The present study aimed to get insights into the mechanisms involved in these changes because the adaptation of uterine blood flow is essential for fetal development. On d 20 of gestation, RT-PCR analysis of uterine arteries showed that PTH/PTHrP receptor (PTH1R) mRNA expression was decreased, whereas that of PTHrP mRNA was increased. This was associated with a redistribution of the PTHrP/PTH1R system, with both PTH1R protein and PTHrP peptide becoming concentrated in the intimal layer of arteries from pregnant rats. On the other hand, the blunted vasorelaxation induced by PTHrP(1–34) in uterine arteries from pregnant rats was specifically restored by indomethacin and a specific cyclooxygenase-2 inhibitor, NS 398. This was associated with an increase in cyclooxygenase-2 expression and in 8-iso-prostaglandin F₂ release when uterine arteries from pregnant rats were exposed to high levels of PTHrP(1–34). Most interestingly, 8-iso-prostaglandin F₂ itself was able to increase PTHrP expression and reduce PTH1R expression in cultured rat aortic smooth muscle cells. These results suggest a local regulation of uterine artery functions by PTHrP during pregnancy resulting from PTH1R redistribution. Moreover, they shed light on a potential role of 8-iso-prostaglandin F₂.