Elsevier

Placenta

Volume 25, Issue 1, January 2004, Pages 53-61
Placenta

PTH/PTHrP Receptor and Mid-molecule PTHrP Regulation of Intrauterine PTHrP: PTH/PTHrP Receptor Antagonism Increases SHR Fetal Weight

https://doi.org/10.1016/j.placenta.2003.08.001Get rights and content

Abstract

Parathyroid hormone-related protein (PTHrP) has important roles in fetal growth and development through stimulation of placental calcium transport, vasodilatation of the uteroplacental vasculature and regulation of cellular growth and differentiation. The growth restricted spontaneously hypertensive rat (SHR) has reduced fetal plasma, placental and amniotic fluid PTHrP concentrations compared to its progenitor, the Wistar Kyoto (WKY) rat. The aim of this study was to determine whether intrauterine PTHrP infusions can restore PTHrP levels and promote SHR fetal growth. PTHrP(1–34), midmolecule PTHrP(67–94), the PTH/PTHrP receptor antagonist [Asn10, Leu11]-PTHrP(7–34) or vehicle were infused via a mini-osmotic pump between 10 and 20 days of gestation into the uterine lumen of SHR and WKY rats. Uterine, placental, amniotic fluid and plasma (fetal and maternal) PTHrP were measured via N-terminal radioimmunoassay. PTH/PTHrP receptor antagonism and mid-molecule PTHrP(67–94) induced endogenous intrauterine PTHrP production with receptor antagonism eliciting a greater and more wide spread effect. The PTH/PTHrP receptor antagonist [Asn10, Leu11]-PTHrP(7–34) acting through a receptor other than the PTH/PTHrP receptor increased SHR fetal and placental weights above vehicle (P<0.05) to that of the WKY and restored SHR amniotic fluid volume (P<0.05). This was associated with a highly significant up regulation of placental, uterine and plasma (fetal and maternal) PTHrP (P<0.05). Modest increases in placental and uterine PTHrP (P<0.05) following intrauterine infusions of PTHrP(1–34) and PTHrP(67–94) had no effect on WKY and SHR fetal weight. Effective growth promoting actions of increased endogenous PTHrP were observed following PTH/PTHrP receptor antagonism rather than exogenous PTHrP administration. A novel finding was that mid-molecule PTHrP also up regulates endogenous intrauterine N-terminal PTHrP production supporting the existence of a mid-molecule receptor. This study highlights that an increase in endogenous uterine, placental and fetal plasma PTHrP following PTH/PTHrP receptor antagonism was associated with increased SHR fetal growth presumably by improving placental growth and function.

Introduction

Both PTHrP and the PTH/PTHrP receptor are essential for fetal development, as disruption of these genes is lethal. PTHrP-deficient mice die at birth due to severe skeletal dysplasia [1], [2]whilst mice with homologous deletion of the PTH/PTHrP receptor gene are growth restricted and die mid-gestation [3], [4]. PTHrP has central roles in placental function and fetal growth. During fetal life PTHrP may act to regulate epithelial cell growth and differentiation [5], normal bone development [1], placental calcium transport [2], [4], [6], [7], uterine smooth muscle tone [8]and fetal-placental vessel tone [9], [10].

Our recent work demonstrates that fetal plasma, placental and amniotic fluid PTHrP concentrations are significantly reduced in association with growth restriction in the spontaneously hypertensive rat (SHR) of the Okamoto strain compared to the Wistar Kyoto (WKY) rat [11]. Other hormonal and metabolic abnormalities are evident in the SHR and these include lower fetal blood glucose and haematocrit, higher blood lactate and altered levels of insulin-like growth factors and their binding proteins [12]. We have shown that the deficiency in placental, uterine and fetal PTHrP may contribute to the compromised fetal growth and developmentobserved in the SHR. Our embryo transfer studies have demonstrated that SHR fetal weight, as well as amniotic fluid PTHrP concentrations, are largely determined by the fetus or gestational tissues and are independent of the maternal environment or hypertension [13]. The SHR is an inbred strain exhibiting fetal growth restriction and spontaneous, genetically determined hypertension, the etiology of which exhibits many similarities to human essential hypertension. The SHR is a model of intrauterine growth restriction that arises spontaneously without nutritional, surgical, or endocrine intervention. Intrauterine growth restriction contributes significantly to perinatal morbidity and mortality as well as a predisposition to diseases including hypertension and diabetes later in life [14]. Studies have also implicated a role for PTHrP in the development and/or maintenance of hypertension in the SHR [15], [16]. Pregnancies complicated by intrauterine growth restriction are characterized by poor placentation, impaired placental blood flow, increased vascular resistance and placental dysfunction that PTHrP is known to influence.

In the present study it was hypothesized that intrauterine PTHrP infusion during the period of rapid fetal growth in the late gestation SHR could restore uterine, placental and fetal PTHrP and by improving placental function thereby increase fetal weight in this model of growth restriction. We administered mid-molecule PTHrP peptides as they have been shown to stimulate ovine [6]placental calcium transport. Infusion of the PTH/PTHrP receptor antagonist was to establish whether the actions of PTHrP are mediated by the PTH/PTHrP receptor and whether the up regulation of gestational tissue and fetal PTHrP improves fetal growth by other mechanisms.

Section snippets

Experimental protocol

This study had the ethical approval of The University of Melbourne's Animal Experimentation Ethics Sub-committee. Nine-week-old female WKY and SHR were obtained from and housed (2 to 4 rats per cage) in the Biological Research Facility, Department of Physiology and Pharmacology, University of Melbourne (Parkville, Victoria, Australia). Animals were subjected to a 12 h light/dark cycle and were fed food pellets and standard tap water ad libitum. They were mated with a breeder of the same strain

SHR and WKY differences in the vehicle group

SHR fetuses in the vehicle treated group weighed 10 per cent less than WKY, had a lower fetal : placental weight ratio and had a greater amniotic fluid volume with no difference in litter size (P<0.005; Figure 1and Table 1). In the vehicle treated group, fetal plasma and amniotic fluid N-terminal PTHrP concentrations were 51 per cent and 40 per cent lower in the SHR compared to the WKY, respectively (P<0.03; Figure 2). In the vehicle group, there were no differences between strains in placental

Discussion

The data presented here are consistent with our recent findings showing that at 20 days of gestation, fetal plasma and amniotic fluid PTHrP concentrations are significantly reduced in the SHR compared to the WKY in association with growth restriction [11], [13]. This supports the hypothesis that PTHrP homeostasis is altered in this strain and may contribute to the compromised fetal growth observed in the SHR. The PTH/PTHrP receptor antagonist [Asn10, Leu11]-PTHrP(7–34) substantially up

Acknowledgments

This study was supported by a National Heart Foundation Grant (MEW, RDN) and a National Health and Medical Research Council of Australia Program Grant (JMM and PWMH). The authors gratefully acknowledge the continuing support of Professor T.J. Martin and the assistance of Georgie Watts. We thank Angela Gibson and Prof Geoffrey Tregear from the Howard Florey Institute of Experimental Physiology and Medicine for measuring total calcium.

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