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Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep
Journal article   Open access   Peer reviewed

Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep

Kenneth A Volk, Robert D Roghair, Felicia Jung, Thomas D Scholz, Fred S Lamb and Jeffrey L Segar
American journal of physiology. Regulatory, integrative and comparative physiology, Vol.298(6), pp.R1607-1614
06/2010
DOI: 10.1152/ajpregu.00824.2009
PMCID: PMC2886704
PMID: 20335378
url
https://doi.org/10.1152/ajpregu.00824.2009View
Published (Version of record) Open Access

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.
 Muscle, Smooth, Vascular - metabolism Endothelin-1 - pharmacology Fetus - metabolism Nitric Oxide Synthase Type III Vasoconstriction - drug effects Coronary Vessels - metabolism Catalase - metabolism Pregnancy Animals Dexamethasone - pharmacology Endothelium - metabolism Glucocorticoids - pharmacology Female Sheep - metabolism Nitric Oxide - metabolism Superoxide Dismutase - metabolism

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