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

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) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ET levels, whereas ET inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O) or hypoxia (11% O) on . 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 antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ET and ET levels were assessed by Western blotting in nonperfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females ( = 0.0528); however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males ( < 0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure ( < 0.01). ET expression was similar among all groups, whereas ET (isoform C) levels were decreased in prenatally hypoxic females ( < 0.05). In prenatally hypoxic males, ET signaling may be essential for tolerance to I/R, whereas in prenatally hypoxic females, ET may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases. 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) 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.