Uteroplacental insufficiency lowers the threshold towards hypoxia-induced cerebral apoptosis in growth-retarded fetal rats.
Infants suffering uteroplacental insufficiency and hypoxic ischemic injury often demonstrate cerebral apoptosis. Our objective was to determine the global effects of uteroplacental insufficiency upon cerebral gene expression of the apoptosis related proteins Bcl-2 and Bax and their role in increasing vulnerability to hypoxia-induced cerebral apoptosis. We therefore caused uteroplacental insufficiency and growth retardation by performing bilateral uterine artery ligation upon pregnant rats 2 days prior to term delivery and elicited further perinatal fetal hypoxia by placing maternal rats in 14% FiO(2) 3 h prior to delivery. We quantified cerebral levels of Bcl-2 and Bax mRNA, lipid peroxidation, caspase-3 activity, and cAMP in control and growth retarded term rat pups that experienced either normoxia or hypoxia. Uteroplacental insufficiency alone caused a significant decrease in cerebral Bcl-2 mRNA levels without altering cerebral Bax mRNA levels, malondialdehyde levels, or caspase-3 activity. In contrast, uteroplacental insufficiency and subsequent fetal hypoxia significantly increased cerebral Bax mRNA levels, lipid peroxidation and caspase-3 activity; Bcl-2 mRNA levels continued to be decreased. Hypoxia alone increased cerebral cAMP levels, whereas uteroplacental insufficiency and subsequent hypoxia decreased cerebral cAMP levels. We speculate that the decrease in Bcl-2 gene expression increases the vulnerability towards cerebral apoptosis in fetal rats exposed initially to uteroplacental insufficiency and subsequent hypoxic stress.
Lane
R H
RH
Department of Pediatrics, UCLA School of Medicine, Mattel Children's Hospital at UCLA, Mental Retardation Research Center, Division of Neonatology and Developmental Biology, 10833 Le Conte Ave B2-375, Los Angeles, CA 90095-1752, USA. rlane@mednet.ucla.edu
Ramirez
R J
RJ
Tsirka
A E
AE
Kloesz
J L
JL
McLaughlin
M K
MK
Gruetzmacher
E M
EM
Devaskar
S U
SU
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000150:complications*; D005333:Fetus / Q000002:abnormalities* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000502:physiology; D002534:Hypoxia, Brain / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000502:physiology; D008315:Malondialdehyde / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010927:Placental Insufficiency / Q000150:complications*; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein
C494828:Bax protein, rat; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D008315:Malondialdehyde; D000242:Cyclic AMP; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases