Costantine Maged M, Ghulmiyyah Labib M, Tamayo Esther, Hankins Gary D V, Saade George R, Longo Monica
Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555-0144, USA.
Am J Obstet Gynecol. 2008 Sep;199(3):250.e1-7. doi: 10.1016/j.ajog.2008.07.002.
The objective of the study was to investigate the transgenerational effect of fetal vascular programming
Homozygous NOS3 knockout and wild type controls (NOS3+/+WT) were cross-bred to obtain heterozygous offspring that developed in (KO-/-) mothers lacking a functional NOS3 (KOM) vs wild-type control mothers (KOP). The first-generation KOM(+/-) and KOP(+/-) female mice were then bred with WT(+/+) males to obtain a second generation (F2). F2 offspring were genotyped and WT(+/+)-F2 mice were then used for in vivo blood pressure and in vitro vascular reactivity studies.
WT-F2 mice born to KOM mothers (KOM-F2WT) had significantly higher systolic blood pressure, mean arterial pressure, and pulse pressure, compared with WT-F2 born to KOP mothers. Male KOM-F2WT offspring had significantly increased response to phenylephrine (PE), compared with male KOP-F2WT. Male offspring had increased contractile responses to PE when compared with female. Acetylcholine responses were decreased in female KOM-F2WT, compared with female KOP-F2WT, but the difference was not statistically significant
Our findings support a transgenerational effect of fetal programming on the vascular phenotype and suggest possible gender specific adaptation.
本研究的目的是调查胎儿血管编程的跨代效应。
将纯合NOS3基因敲除小鼠与野生型对照（NOS3+/+WT）进行杂交，以获得杂合子后代，这些后代在缺乏功能性NOS3的（KO-/-）母亲（KOM）体内发育，与野生型对照母亲（KOP）体内发育的后代进行对比。然后将第一代KOM(+/-)和KOP(+/-)雌性小鼠与WT(+/+)雄性小鼠交配，以获得第二代（F2）。对F2后代进行基因分型，然后将WT(+/+)-F2小鼠用于体内血压和体外血管反应性研究。
与KOP母亲所生的WT-F2小鼠相比，KOM母亲所生的WT-F2小鼠（KOM-F2WT）的收缩压、平均动脉压和脉压显著更高。与雄性KOP-F2WT相比，雄性KOM-F2WT后代对去氧肾上腺素（PE）的反应显著增强。与雌性相比，雄性后代对PE的收缩反应增强。与雌性KOP-F2WT相比，雌性KOM-F2WT对乙酰胆碱的反应降低，但差异无统计学意义。
我们的研究结果支持胎儿编程对血管表型的跨代效应，并表明可能存在性别特异性适应。
