PTH/PTHrP receptor and mid-molecule PTHrP regulation of intrauterine PTHrP: PTH/PTHrP receptor antagonism increases SHR fetal weight.
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 [Asn(10), Leu(11)]-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 [Asn(10), Leu(11)]-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.
Wlodek
M E
ME
Department of Physiology, The University of Melbourne, Grattan Street, Carlton,Victoria, Australia 3010. m.wlodek@unimelb.edu.au
Di Nicolantonio
R
R
Westcott
K T
KT
Farrugia
W
W
Ho
P W M
PW
Moseley
J M
JM
D000653:Amniotic Fluid; D000818:Animals; D005314:Embryonic and Fetal Development / Q000187:drug effects / Q000502:physiology; D005260:Female; D020567:Fetal Weight; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage; D010920:Placenta; D011247:Pregnancy; D011506:Proteins / Q000008:administration & dosage; D011863:Radioimmunoassay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; C064776:parathyroid hormone-related protein (7-34)amide