Carbon Monoxide Promotes Proliferation of Uterine Natural Killer Cells and Remodeling of Spiral Arteries in Pregnant Hypertensive Heme Oxygenase-1 Mutant Mice

Heme Oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) promote implantation and placentation. Pregnancy disorders such as preeclampsia and intrauterine growth restriction are linked to both HO-1 diminution and impaired remodeling of maternal spiral arteries (SAs). Here, we investigated whether CO is able to prevent preeclampsia and intrauterine growth restriction through the modulation of uterine natural killer (uNK) cells that are necessary for initiation of SA remodeling. Hmox1(+/-) or Hmox1(-/-) implantations presented fewer uNK cell numbers and lower expression of uNK-related angiogeneic factors compared with Hmox1(+/+) sites. Quantitative histology revealed that Hmox1(+/-) and Hmox1(-/-) implantations had shallow SA development that was accompanied by intrauterine growth restriction and gestational hypertension. Application of CO at low dose during early to midgestation prevented intrauterine growth restriction in Hmox1(+/-) mothers, this being associated with enhanced in situ proliferation of uNK cells and normalization of angiogenic parameters. Most importantly, CO improved SA remodeling and normalized blood pressure, ensuring a proper fetal growth. Thus, CO emerges as a key molecular player in pregnancy success by modulating uNK cells, which results in promotion of SA remodeling, adequate fetal support/growth, and prevention of hypertension.