Effect of Heme Oxygenase-1 Deficiency on Placental Development

Abstract

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 preeclampsia. 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 constitutive 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.

Progesterone and HMOX-1 promote fetal growth by CD8+ T cell modulation

“…Placental insufficiency and fetal growth restriction have previously been observed in a number of mouse models. However, these models were largely restricted to the use of genetically engineered mice lacking particular genes, such as endothelial nitric oxide synthase (51,52) and Hmox1 (31). Compared with these, the model for fetal-growth restriction upon stress challenge used here is of greater clinical relevance, given that the causative mechanisms were mounted endogenously.…”

“…In addition to progesterone, emerging evidence suggests that heme oxygenase 1 (HMOX-1), an enzyme that catalyzes the degradation of heme into carbon monoxide, biliverdin, and iron, is also a critical mediator of pregnancy maintenance and placental function (29)(30)(31)(32). HMOX-1 is expressed in most tissues, including the placenta in mice and humans (29,31), and acts as a critical factor for promoting vasculature formation and immune homeoIntrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies.…”

“…HMOX-1 is expressed in most tissues, including the placenta in mice and humans (29,31), and acts as a critical factor for promoting vasculature formation and immune homeoIntrauterine growth restriction (IUGR) affects up to 10% of pregnancies in Western societies. IUGR is a strong predictor of reduced short-term neonatal survival and impairs long-term health in children.…”

“…Further, these changes in fetal weight were accompanied by reduced placental L/Jz ratios due to a decrease in labyrinth size ( Figure 2C). stasis by inhibiting overshooting reactions in a number of tissues in the body (31)(32)(33). Both progesterone and HMOX-1 can suppress CD4 + effector T cell responses and induce the generation of CD4 + Tregs (34)(35)(36)(37), which also promote maternal immune tolerance to the fetus (38,39).…”

The Effect of the Gly139His, Gly143His, and Ser142His Mouse Heme Oxygenase‐1 Mutants on the HO Reaction In Vivo and In Vitro

“…Due to the potent antioxidant activity of biliverdin and bilirubin, and to the cytoprotective actions of carbon monoxide on vascular endothelium and nerve cells, it is widely accepted that upregulation of HO-1 causes beneficial effects (Stocker et al, 1987;Verma et al, 1993;Brouard et al, 2000;Colle et al, 2008;Mancuso and Barone, 2009;Ryter and Choi, 2009;Gozzelino et al, 2010). In contrast, the lack of, or inhibition of, HO-1 generally accelerates growth retardation, anemia, and tissue iron deposition, as seen in HO-1-deficient humans and mice (Poss and Tonegawa, 1997a,b;Kapturczak et al, 2004;Zhao et al, 2009).…”