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Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep. Am J Physiol Regul Integr Comp Physiol 2010 Jun;298(6):R1607-14

Date

03/26/2010

Pubmed ID

20335378

Pubmed Central ID

PMC2886704

DOI

10.1152/ajpregu.00824.2009

Scopus ID

2-s2.0-77952719685   5 Citations

Abstract

Exposure of the early-gestation ovine fetus to exogenous glucocorticoids induces changes in postnatal cardiovascular physiology. We sought to characterize coronary artery vascular function in this model by elucidating the contribution of nitric oxide and reactive oxygen species to altered coronary vascular reactivity and examining the proliferative potential of coronary artery vascular smooth muscle cells. Dexamethasone (dex, 0.28 mg x kg(-1) x day(-1) for 48 h) was administered to pregnant ewes at 27-28-day gestation (term 145 days). Coronary arteries were isolated from 1- to 2-wk-old dex-exposed offspring and aged-matched controls. Compared with controls, coronary arteries from dex-exposed lambs demonstrated enhanced vasoconstriction to endothelin-1 and ACh that was abolished by endothelial removal or preincubation with the nitric oxide synthase inhibitor L-NNA, membrane-permeable superoxide dismutase + catalase, or apamin + charybdotoxin, but not indomethacin. The rate of coronary vascular smooth muscle cell (VSMC) proliferation was also significantly greater in dex-exposed lambs. Protein levels of the proliferating cell nuclear antigen were increased and alpha-smooth muscle actin decreased in dex-exposed coronary VSMC, consistent with a proliferative state. Finally, expression of the NADPH oxidase Nox 4, but not Nox 1, mRNA was also decreased in coronary VSMC from dex-exposed lambs. These findings suggest an important interaction exists between early-gestation glucocorticoid exposure and reactive oxygen species that is associated with alterations in endothelial function and coronary VSMC proliferation. These changes in coronary physiology are consistent with those associated with the development of atherosclerosis and may provide an important link between an adverse intrauterine environment and increased risk for coronary artery disease.

Author List

Volk KA, Roghair RD, Jung F, Scholz TD, Lamb FS, Segar JL

Author

Jeffrey L. Segar MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Catalase
Coronary Vessels
Dexamethasone
Endothelin-1
Endothelium
Female
Fetus
Glucocorticoids
Muscle, Smooth, Vascular
Nitric Oxide
Nitric Oxide Synthase Type III
Pregnancy
Sheep
Superoxide Dismutase
Vasoconstriction
jenkins-FCD Prod-478 d1509cf07a111124a2d122fd3df854cc0b993c00