Endocrine Abstracts (2004) 7 OC7

Placental endokinins may play a paracrine role on the placental vasculature

NM Page1, SM Gardiner2, DW Morrish3, IT Manyonda4 & PJ Lowry1

1School of Animal & Microbial Sciences, University of Reading, Reading, UK; 2School of Biomedical Sciences, University of Nottingham, Nottingham, UK; 3Department of Medicine, University of Alberta, Canada; 4St. George's Hospital, London, UK.

Substance P (SP), neurokinin A and neurokinin B (NKB) are vasoactive tachykinins, believed to exert their effects by release from nerve endings to activate three neurokinin receptors. We have found the major source of NKB (TAC3) expression to be the placenta which results in elevated maternal blood levels in pre-eclampsia. Placental NKB appears to increase blood flow in the placenta and uterus but causes pressor effects in the peripheral circulation. Whilst the placenta, is devoid of SP (TAC1) expression, it expresses the novel tachykinin (TAC4) gene which gives rise to a SP-like peptide, endokinin A/B, which we have found to display equivalent affinity and agonist activity for the three NK receptors as substance P. In rats, EKA/B are shown to be vasoactive causing short-lived falls in mean arterial blood pressure, tachycardia, mesenteric vasoconstriction, and marked hindquarter vasodilatation (Page et al. 2003). Cloning of the mouse, rat and rabbit TAC4 genes reveals significant diversity in this group of endokinin peptides, demonstrating the existence in mammals of at least five different NK1 receptor preferring peptides. Extra diversity is created by splice variants to produce either EKA/B on its own or with other tachykinin-like peptides. In the human placenta, placental trophoblast and fetal endothelial cell lines we find the expression of TAC3, and TAC4 (with their potential direct secretion into the placental vasculature). Preliminary evidence also indicates that placental TAC3 (P = 0.0009, ANOVA), TAC4 (P = 0.0004) and the NK3 receptor (P = 0.0265) are significantly up-regulated in pre-eclampsia at term compared to controls. We propose that the local production of vasoactive NKB and EKA/B could have importance in determining placental blood flow and their up-regulation during pre-eclampsia could help induce placental and uterine vasodilation and thus help increase the nourishment of the fetus.

Page et al. 2003 PNAS100:6245.

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