Heme oxygenase-1 is critically involved in placentation, spiral artery remodeling, and blood pressure regulation during murine pregnancy

Abstract

The onset of pregnancy implies the appearance of a new organ, the placenta. One main function of the placenta is to supply oxygen to the fetus via hemoproteins. In this review, we highlight the importance of the enzyme heme oxygenase-1 (HO-1) for pregnancy to be established and maintained. HO-1 expression is pivotal to promote placental function and fetal development, thus determining the success of pregnancy. The deletion of the gene Hmox1 in mice leads to inadequate remodeling of spiral arteries and suboptimal placentation followed by intrauterine growth restriction (IUGR) and fetal lethality. A partial Hmox1 deletion leads to IUGR as well, with heterozygote and wild-type fetuses being born, but Hmox1–/– significantly below the expected Mendelian rate. This strong phenotype is associated with diminished number of pregnancy-protective uterine natural killer (uNK) cells. Pregnant heterozygote females develop gestational hypertension. The protective HO-1 effects on placentation and fetal growth can be mimicked by the exogenous administration of carbon monoxide (CO), a product of heme catalyzed by HO-1. CO application promotes the in situ proliferation of uNK cells, restores placentation and fetal growth, while normalizing blood pressure. Similarly, HO-1 inhibition provokes hypertension in pregnant rats. The HO-1/CO axis plays a pivotal role in sustaining pregnancy and aids in the understanding of the biology of pregnancy and reveals a promising therapeutic application in the treatment of pregnancy complications.

CD74-Downregulation of Placental Macrophage-Trophoblastic Interactions in Preeclampsia

“…Glucose regulates the Heme oxygenase-1 that is a central player for immune regulation. 44 Furthermore, glucose regulates the exosomal signaling by placental cells and the release of cytokines. 45 It might be that a dysregulation in glucose metabolism at first trimester in pregnancies has adverse outcome on the CD74 expression and therefore associates with placental insufficiency.…”

Modulation of antigen processing by haem‐oxygenase 1. Implications on inflammation and tolerance

“…Another study showed decreased placenta size and weight, as well as impaired cell viability in mice heterozygous ( Hmox1 +/− ) for HO‐1 . Along these lines, it has been shown that both Hmox1 +/− and Hmox1 −/− mice show an impairment in uterine natural killer (uNK) ‐dependent maternal spiral arteries remodeling during implantation because of reduced numbers of uNK . Interestingly, treatement of Hmox1 +/− mice with low doses of CO improved both uNK proliferation, spiral arteries remodelling and also stabilized blood presure, suggesting that this gas plays a key role during uNK‐dependent intrauterine growth .…”

“…141,142 Along these lines, it has been shown that both Hmox1 +/À and Hmox1 À/À mice show an impairment in uterine natural killer (uNK) -dependent maternal spiral arteries remodeling during implantation because of reduced numbers of uNK. 143,144 Interestingly, treatement of Hmox1 +/À mice with low doses of CO improved both uNK proliferation, spiral arteries remodelling and also stabilized blood presure, suggesting that this gas plays a key role during uNK-dependent intrauterine growth. 143,144 Similar data were obtained in a trophoblastic stem cell line that resembles the development of trophoblasts into giant cells, which showed that HO-1 inhibition compromises cell viability and their ability to differentiate.…”

Heme Oxygenase-1 Is Not Decreased in Preeclamptic Placenta and Does Not Negatively Regulate Placental Soluble fms-Like Tyrosine Kinase-1 or Soluble Endoglin Secretion

“…In mouse models where HO-1 is genetically deleted, there is inadequate remodeling of the spiral arteries, diminished numbers of uterine natural killer cells at the maternal fetal interface, and fetal growth restriction. [33][34][35] Furthermore, mothers carrying an HO-1 +/− heterozygote develop hypertension in the latter stages of their pregnancy. 34 However, whether these intriguing findings are relevant to early human placentation is yet to be proven.…”