Prenatal hypoxia programs vascular endothelin‐1 activity in adult offspring

Hypoxia during pregnancy causes long‐term alterations in vascular function, characterized by diminished nitric oxide (NO) signaling and enhanced responsiveness to vasoconstrictors in adult offspring. In the present study, we hypothesized that prenatal hypoxia would lead to increased synthesis of endothelin‐1 (ET‐1) from its inactive precursor big endothelin‐1 (bET‐1) via endothelin converting enzyme (ECE) and matrix metalloproteinases (MMP) in adult offspring. Dams were exposed to hypoxia (11% O 2 ) from gestational day 15–21; controls were maintained at 21% O 2 levels throughout pregnancy. At 4 months of age, offspring mesenteric vascular responses to administered bET‐1 were assessed by wire myography. In control but not hypoxic offspring, L‐NAME (NO synthase inhibitor) potentiated bET‐1 vasoconstrictor response. In males, treatment with the MMP inhibitor GM6001 cause greater inhibition in IUGR offspring; the ECE inhibitor phosphoramidon completely abolished responses in both groups. In contrast, IUGR females, but not control females, had negligible conversion of bET‐1 to active ET‐1, and this was reversible with GM6001 treatment. These results suggest that bET‐1 conversion to active ET‐1 is altered by prenatal hypoxia, and could signify an underlying vascular dysfunction in these animals. This work is supported by the Canadian Institutes of Health Research and Alberta Innovates Health Solutions.