Prenatal hypoxia causes long-term alterations in vascular endothelin-1 function in aged male, but not female, offspring.

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.

• Authors: Stephane L Bourque, Ferrante S Gragasin, Anita L Quon, Yael Mansour, Jude S Morton, Sandra T Davidge
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 62 Issue 4 Pg. 753-8 (Oct 2013) ISSN: 1524-4563 [Electronic] United States
• PMID: 23940196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• Nitric Oxide

Topics

• Animals
• Blood Pressure (drug effects, physiology)
• Dose-Response Relationship, Drug
• Endothelin-1 (pharmacology)
• Endothelium, Vascular (drug effects, physiopathology)
• Female
• Fetal Growth Retardation (etiology, physiopathology)
• Hypoxia (complications, physiopathology)
• Male
• Mesenteric Arteries (drug effects, physiopathology)
• Nitric Oxide (metabolism)
• Pregnancy
• Prenatal Exposure Delayed Effects (physiopathology)
• Rats
• Rats, Sprague-Dawley
• Sex Factors
• Vasoconstriction (drug effects, physiology)