Uteroplacental restriction in the rat impairs fetal growth in association with alterations in placental growth factors including PTHrP

Abstract

During pregnancy, parathyroid hormone-related protein (PTHrP) is one of many growth factors that play important roles to promote fetal growth and development, including stimulation of placental calcium transport. Angiotensin II, acting through the AT(1a) receptor, is also known to promote placental growth. We examined the effects of bilateral uterine artery and vein ligation (restriction), which mimics placental insufficiency in humans, on growth, intrauterine PTHrP, placental AT(1a), and pup calcium. Growth restriction was surgically induced on day 18 of pregnancy in Wistar-Kyoto female rats by uterine vessel ligation. Uteroplacental insufficiency reduced fetal body weight by 15% and litter size (P < 0.001) compared with the control rats with no effect on placental weight or amniotic fluid volume. Uteroplacental insufficiency reduced placental PTHrP content by 46%, with increases in PTHrP (by 2.6-fold), parathyroid hormone (PTH)/PTHrP receptor (by 11.6-fold), and AT(1a) (by 1.7-fold) relative mRNA in placenta following restriction compared with results in control (P < 0.05). There were no alterations in uterine PTHrP and PTH/PTHrP receptor mRNA expression. Maternal and fetal plasma PTHrP and calcium concentrations were unchanged. Although fetal total body calcium was not altered, placental restriction altered perinatal calcium homeostasis, as evidenced by lower pup total body calcium after birth (P < 0.05). The increased uterine and amniotic fluid PTHrP (P < 0.05) may be an attempt to compensate for the induced impaired placental function. The present study demonstrates that uteroplacental insufficiency alters intrauterine PTHrP, placental AT(1a) expression, and perinatal calcium in association with a reduction in fetal growth. Uteroplacental insufficiency may provide an important model for exploring the early origins of adult diseases.

Uteroplacental insufficiency and reducing litter size alters skeletal muscle mitochondrial biogenesis in a sex-specific manner in the adult rat

“…A vaginal impedence reader (model MK-10B; Mukomachi Kikai, Osaka, Japan) was used to determine whether females were in the appropriate stage of the estrous cycle for mating, as described previously (20,40,41). The following morning, the presence of sperm in vaginal smears was taken as day 1 of pregnancy.…”

Low female birth weight and advanced maternal age programme alterations in next-generation blastocyst development

“…A vaginal impedance reader (model MK-10B, Mukomachi Kikai, Osaka, Japan) was used to determine the time of oestrus for mating as described previously (Wlodek et al 2005. Female WKY rats (F0) were mated between 18 and 24 weeks of age.…”

“…Female WKY rats (F0) were mated between 18 and 24 weeks of age. On day 18 of gestation, rats underwent sham (control) or bilateral uterine vessel ligation (restricted) surgery (Wlodek et al 2005. Rats gave birth naturally at term (day 22) to F1 control and growth-restricted offspring (born small) respectively.…”

“…Mating success was confirmed by the presence of a vaginal plug after mating, and the following morning was considered day 0.5 of pregnancy. All female body weights and dimensions were measured before mating and at postmortem (day 4.5 of pregnancy) (Wlodek et al 2005 after they were killed by CO 2 inhalation. Plasma insulin concentrations were measured in duplicate using a rat insulin RIA kit (Millipore, Abacus ALS, Brisbane, QLD, Australia) .…”

“…Our established rat model of uteroplacental insufficiency mimics intrauterine growth restriction similar to that observed in the Western world (Wlodek et al 2005. Both F1 male and female offspring have organ deficits, but only F1 male offspring develop hypertension and metabolic dysfunction in adult life (Wadley et al 2008, Moritz et al 2009).…”