Sex-specific effects of prenatal hypoxia on the cardiac endothelin system in adult offspring

Abstract

Fetal hypoxia, a major consequence of complicated pregnancies, impairs offspring cardiac tolerance to ischemia-reperfusion (I/R) insult; however, the mechanisms remain unknown. Endothelin-1 (ET-1) signaling through the endothelin A receptors (ET_A) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ET_A levels, whereas ET_A inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O₂) or hypoxia (11% O₂) on gestational days 15-21. Offspring were aged to 4 mo, and hearts were aerobically perfused or subjected to ex vivo I/R, with or without preinfusion with an ET_A antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ET_A and ET_B levels were assessed by Western blotting in nonperfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females (P = 0.0528); however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males (P < 0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure (P < 0.01). ET_A expression was similar among all groups, whereas ET_B (isoform C) levels were decreased in prenatally hypoxic females (P < 0.05). In prenatally hypoxic males, ET_A signaling may be essential for tolerance to I/R, whereas in prenatally hypoxic females, ET_A may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases.NEW & NOTEWORTHY We demonstrated that prenatal hypoxia (a common condition of pregnancy) can have profound differential effects on treatment strategies in adult cardiovascular disease. Our data using a rat model of prenatal hypoxia demonstrated that, as adults, although inhibition of endothelin (ET_A) receptors before an ex vivo cardiac ischemic insult improved recovery in females, it strikingly prevented recovery in males. Our data indicate a sex-specific effect of prenatal hypoxia on the cardiac ET-1 system in adult offspring.

Keywords: cardiac ischemia-reperfusion injury; developmental origins of health and disease; endothelin-1; pregnancy complications; prenatal hypoxia.