Effect of heme oxygenase-1 deficiency on placental development.
Heme oxygenase (HO) is the rate-limiting enzyme in the heme catabolic pathway and highly expressed in the placenta. Deficiencies in HO-1, the inducible isoform, have been associated with pregnancy disorders, such as recurrent miscarriages, intrauterine growth retardation, and pre-eclampsia. The aim of this study was to identify if a deficiency in HO-1 affects placental development using a mouse model. When HO-1 heterozygote (Het, HO-1(+/-)) mice were cross-bred, an extremely low birth rate in homozygote (Mut, HO-1(-/-)) offspring (2.4%) and small litter sizes were observed. Placentas and fetuses from Het cross-breedings were relatively smaller and weighed less than those from wild-type (WT) cross-breedings at E12.5 and E15.5. Furthermore, Het placentas had significantly less HO-1 mRNA and protein levels than WT placentas, but no significant differences in placental HO activity. Interestingly, HO-2, the constituitive HO isoform, as well as iNOS and eNOS expression were significantly upregulated in Het placentas. Histological examination showed that the junctional zone (JZ) of Het placentas were markedly thinner than those of WT placentas and appeared to be due to an increase in apoptosis. Immunohistochemistry revealed that HO-1-expressing cells were located primarily in the JZ of Het placentas, specifically in the spongiotrophoblast layer. In addition, diastolic blood pressures and plasma soluble VEGFR-1 (sFlt-1) levels were significantly elevated in pregnant Het mice. We conclude that a partial deficiency in HO-1 is associated with morphological changes in the placenta and elevations in maternal diastolic blood pressure and plasma sFlt-1 levels, despite a compensatory increase in HO-2 expression.
Zhao
H
H
Dept. of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. huizhao2@stanford.edu
Wong
R J
RJ
Kalish
F S
FS
Nayak
N R
NR
Stevenson
D K
DK
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001158:Arteries / Q000473:pathology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics; D005260:Female; D005313:Fetal Death / Q000235:genetics; D020567:Fetal Weight / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D008098:Litter Size / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D009929:Organ Size / Q000235:genetics; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D010929:Placentation; D011247:Pregnancy; D014327:Trophoblasts / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood
D051792:Basic Helix-Loop-Helix Proteins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D040281:Vascular Endothelial Growth Factor Receptor-1; C489311:Ascl2 protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C105245:heme oxygenase-2; C501163:Flt1 protein, mouse
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