Endothelin Receptor A Antagonism and Fetal Growth in Endothelial Nitric Oxide Synthase Gene Knockout Maternal and Fetal Mice

Abstract

Fetal growth restriction (FGR) is commonly associated with perinatal morbidity and mortality. Nitric oxide (NO) deficiency increases endothelin-1 (ET-1) production, and this increased ET-1 may contribute to the pathophysiology of NO deficiency-induced FGR. Using an endothelial NO synthase knockout mouse model of FGR, we sought to determine (a) the relative importance of maternal versus conceptus (fetal and placental) NO deficiency and (b) the contribution of ET-1 to the pathogenesis of FGR in this model. Fetal growth restriction occurred both with NO-deficient conceptuses in the setting of maternal NO production and with maternal NO deficiency in the setting of NO-producing conceptuses. Placental ET-1 expression was increased in NO-deficient dams, ET receptor A (ETA) production increased in endothelial nitric oxide synthase(+/-) placentas, and antagonism of ETA prevented FGR. These results demonstrate that both maternal and conceptus NO deficiency can contribute to FGR and suggest a role for ETA antagonists as therapeutic agents in FGR.

Gasotransmitters in pregnancy: from conception to uterine involution†

“…Pregnant women express more uterine artery eNOS than age-matched nonpregnant women [187,188], and E 2 promotes uterine artery eNOS accumulation in ovariectomized sheep [189]. Moreover, eNOS knockout mice are hypertensive [190]. These studies suggest decreased paraventricular nNOS helps maintain vascular resistance to balance the increased peripheral vasodilation necessary for pregnancy (Figure 6A).…”

“…VEGFR2 increases PI3Kdependent Ca 2+ entry, which stimulates eNOS independently of ERK1/2, Akt, or eNOS S1177 phosphorylation [204,205]. Pregnant eNOS knockout mice exhibit IUGR that is rescued by administration of an endothelin receptor A antagonist [190]. Similar to fallopian tube peristalsis, maternal uterine artery expansion could involve dynamic interplay between endothelin-dependent contraction and eNOS-dependent relaxation.…”