Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep.
Coronary endothelial function and vascular smooth muscle proliferation are programmed by early-gestation dexamethasone exposure in sheep.
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绵羊妊娠早期暴露于地塞米松可调节冠状动脉内皮功能和血管平滑肌增殖。
DOI：
10.1152/ajpregu.00824.2009
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
Segar,JeffreyL
中科院分区：
文献类型：
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作者：
Volk,KennethA;Roghair,RobertD;Jung,Felicia;Scholz,ThomasD;Lamb,FredS;Segar,JeffreyL
妊娠早期绵羊胎儿暴露于外源性糖皮质激素诱导出生后心血管生理变化。我们试图通过阐明一氧化氮和活性氧对冠状动脉血管反应性改变的贡献以及检查冠状动脉血管平滑肌细胞的增殖潜力来表征该模型中的冠状动脉血管功能。妊娠母羊在妊娠27-28 d（足月145 d）时给予地塞米松（Dexamethasone，dex，0.28 mg·kg-1·d-1，共48 h）。冠状动脉分离自1- 2周龄dex暴露的后代和年龄匹配的对照组。与对照组相比，从右旋糖酐暴露羔羊的冠状动脉表现出增强的血管收缩内皮素-1和乙酰胆碱被废除内皮细胞去除或预孵育的一氧化氮合酶的catenorl-NNA，膜渗透性超氧化物歧化酶+过氧化氢酶，或apamin + charybdotoxin，但不是吲哚美辛。冠状动脉血管平滑肌细胞（VSMC）的增殖率也显着更大的右旋糖酐暴露的羔羊。在dex暴露的冠状动脉VSMC中，增殖细胞核抗原的蛋白水平增加，α-平滑肌肌动蛋白减少，与增殖状态一致。最后，NADPH氧化酶Nox 4，但不Nox 1，mRNA的表达也减少了从dex暴露的羔羊冠状动脉VSMC。这些发现表明，妊娠早期糖皮质激素暴露与活性氧之间存在重要的相互作用，这与内皮功能的改变和冠状动脉VSMC增殖有关。冠状动脉生理学的这些变化与动脉粥样硬化的发展相关，并可能提供不利的宫内环境和冠状动脉疾病风险增加之间的重要联系。
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·kg−1·day−1for 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 inhibitorl-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 α-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.