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Prenatal hypoxia causes long-term alterations in vascular endothelin-1 function in aged male, but not female,
Stephane L Bourque1, Ferrante S Gragasin, Anita L Quon
1Department of Obstetrics and Gynecology, 232 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. Sandra.davidge@ualberta.ca.
Insights
Prenatal hypoxia alters fetal growth, leading to intrauterine growth restriction (IUGR). IUGR offspring exhibit altered vascular endothelin-1 (ET-1) signaling, particularly in males, impacting blood pressure regulation and long-term vascular health.
Area of Science:
- Cardiovascular Physiology
- Developmental Biology
- Endocrinology
Background:
- Prenatal hypoxia is a known cause of intrauterine growth restriction (IUGR).
- IUGR can lead to long-term health issues, including vascular dysfunction.
- Endothelin-1 (ET-1) signaling plays a critical role in regulating vascular tone.
Purpose of the Study:
- To investigate the long-term effects of prenatal hypoxia-induced IUGR on vascular ET-1 signaling in offspring.
- To determine if IUGR alters the response to ET-1 and its precursors in mesenteric arteries.
- To explore sex-specific differences in vascular responses to ET-1 signaling in IUGR offspring.
Main Methods:
- Wire myography was used to assess isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1.
- Experiments involved nitric oxide synthase inhibition and the use of various enzyme inhibitors.
- In vivo systolic blood pressure responses to ET-1 antagonism were measured.
Main Results:
- Male IUGR offspring showed significantly increased vasoconstriction to bET-1 compared to controls.
- Nitric oxide synthase inhibition had a greater potentiating effect on bET-1 vasoconstriction in control males versus IUGR males.
- Vascular responses to bET-1 were similar in female IUGR and control offspring.
- ET-converting enzyme inhibition abolished vascular responses to bET-1 in both control and IUGR groups.
- IUGR male offspring exhibited greater in vivo blood pressure reduction with ET-1 antagonism.
Conclusions:
- Prenatal hypoxia programs altered vascular ET-1 function in IUGR offspring.
- Sex differences exist in the long-term vascular consequences of developmental stress.
- ET-1 converting enzyme is crucial for mediating vascular responses to bET-1 in this model.
Abstract:
Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1-induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N(G)-nitro-arginine-methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N(G)-nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymostatin, the gelatinase inhibitor GM6001, or the neutral endopeptidase inhibitor thiorphan did not alter responses to bET-1; however, the ET-converting enzyme inhibitor CGS35066 almost completely abolished vascular responses to bET-1 in control and IUGR groups. Systolic blood pressure in IUGR male offspring was more responsive to ET-1 antagonism in vivo compared with controls (-9 versus -4 mm Hg; n=5 per group; P=0.02); no such differences were observed in female offspring (n=5-6 per group). These results demonstrate that vascular ET-1 function is programmed by prenatal hypoxia and provide further insights into the sex differences in the long-term vascular effects of developmental stressors.
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