Effects of Antenatal Uteroplacental Hypoperfusion on Neonatal Microvascularisation and Excitotoxin Sensitivity in Mice

Abstract

Vascular intrauterine growth restriction (IUGR) occurs in about 5% of pregnancies and may reduce the incidence of periventricular leukomalacia in preterm newborns. We evaluated neonatal excitotoxicity in a murine model of vascular IUGR involving unilateral uterine ligation on embryonic day (E)13.5. Birth weight was significantly decreased in the ligation group compared with the sham group (p Ͻ 0.001). VEGFs, VEGF receptors (VEGFRs), and NMDA receptor subunit mRNAs in brain extracts were assayed using quantitative RT-PCR. Ligation was associated with increased mRNAs for the vascular marker PECAM-1 on postnatal day (PD)2 and VEGFR-3 on PD2 and PD10, contrasting with decreased VEGFA and VEGFC on PD10. Microvessel density was increased on PD7. Ligated and sham pups received intracerebral ibotenate (NMDA agonist) on PD2 or PD10.

Neurological outcomes of animal models of uterine artery ligation and relevance to human intrauterine growth restriction: a systematic review

“…This period represents the onset of rapid fetal growth and corresponds to the beginning of the third trimester in human pregnancy . Uterine artery ligation was performed at mid‐gestation (28–30d) in guinea pigs and at embryonic day 13 (E13) in mice …”

“…This leads to a gradient in the fetal size, with the smallest rats being closest to the ligation site and the largest being more distal . Reduced body weight was observed until postnatal day 21 (PN21) in rats and until PN10 in mice . In rats, placental insufficiency did not result in a concomitant reduction in brain weight and, thus, resulted in an increased ratio of brain weight to body weight .…”

“…In a ‘double hit’ protocol using uterine artery ligation and intracerebral ibotenate (NMDA antagonist) injection, moderate growth restriction was found to be neuroprotective against excitotoxic white matter lesions at PN10 . Similarly, mice with placental insufficiency that were injected with ibotenate at PN2 experienced less cortical damage and WMD than comparison mice . However, rats with placental insufficiency were not protected, compared with sham animals, when injected with ibotenate at PN10.…”

“…17,22,23 Reduced body weight was observed until postnatal day 21 (PN21) in rats 24 and until PN10 in mice. 21 In rats, placental insufficiency did not result in a concomitant reduction in brain weight and, thus, resulted in an increased ratio of brain weight to body weight. 24 In guinea pigs fetuses with placental insufficiency, there was a significant reduction in whole brain weight, but this reduction was less than that seen in body weight.…”

“…17 Uterine artery ligation was performed at mid-gestation (28-30d) in guinea pigs [18][19][20] and at embryonic day 13 (E13) in mice. 21 The closer the fetus is to the ligation, the more significant the effect of the insufficiency and growth restriction. This leads to a gradient in the fetal size, with the smallest rats being closest to the ligation site and the largest being more distal.…”