Abstract
Abstract Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are linked to impaired remodeling of maternal spiral arteries (SA). We previously introduced Heme Oxygenase-1 (HO-1) as a positive modulator of pregnancy. Its main mediator, carbon monoxide, could mimic HO-1 protective effects in a mouse model of Hmox1 genetic deficiency. Here, we investigated whether HO-1 deficiency is related to gestational hypertension and if CO is able to prevent PE and IUGR through the modulation of uterine NK cells (uNK) 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 than Hmox1+/+ sites. Quantitative histology revealed that Hmox1+/- and Hmox1-/- implantations had shallow SA development. This was accompanied by IUGR and gestational hypertension. Application of CO at low dose during early to mid-gestation prevented IUGR in Hmox1+/- mothers, being this associated with enhanced in situ proliferation of uNKs 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 uNKs, which results in promotion of SA remodeling, adequate fetal support/growth and prevention of gestational hypertension.
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