van der Linde S, Romano T, Wadley G, Jeffries A J, Wlodek M E, Hryciw D H
1Department of Physiology,The University of Melbourne,Parkville,VIC,Australia.
2Department of Human Biosciences,Latrobe University,Bundoora,VIC,Australia.
J Dev Orig Health Dis. 2014 Aug;5(4):314-21. doi: 10.1017/S2040174414000245.
Uteroplacental insufficiency resulting in intrauterine growth restriction has been associated with the development of cardiovascular disease, coronary heart disease and increased blood pressure, particularly in males. The molecular mechanisms that result in the programming of these phenotypes are not clear. This study investigated the expression of cardiac JAK/STAT signalling genes in growth restricted offspring born small due to uteroplacental insufficiency. Bilateral uterine vessel ligation was performed on day 18 of pregnancy to induce growth restriction (Restricted) or sham surgery (Control). Cardiac tissue at embryonic day (E) 20, postnatal day (PN) 1, PN7 and PN35 in male and female Wistar (WKY) rats (n=7-10 per group per age) was isolated and mRNA extracted. In the heart, there was an effect of age for males for all genes examined there was a decrease in expression after PN1. With females, JAK2 expression was significantly reduced after E20, while PI3K in females was increased at E30 and PN35. Further, mRNA expression was significantly altered in JAK/STAT signalling targets in Restricteds in a sex-specific manner. Compared with Controls, in males, JAK2 and STAT3 were significantly reduced in the Restricted, while in females SOCS3 was significantly increased and PI3K significantly decreased in the Restricted offspring. Finally, there were specific differences in the levels of gene expression within the JAK/STAT pathway when comparing males to females. Thus, growth restriction alters specific targets in the JAK/STAT signalling pathway, with altered JAK2 and STAT3 potentially contributing to the increased risk of cardiovascular disease in the growth restricted males.
导致子宫内生长受限的子宫胎盘功能不全与心血管疾病、冠心病及血压升高的发生有关，尤其是在男性中。导致这些表型编程的分子机制尚不清楚。本研究调查了因子宫胎盘功能不全而出生体重小的生长受限后代心脏中JAK/STAT信号基因的表达。在妊娠第18天进行双侧子宫血管结扎以诱导生长受限（受限组）或假手术（对照组）。分离雄性和雌性Wistar（WKY）大鼠（每个年龄组每组n = 7 - 10）在胚胎期（E）20、出生后第1天（PN）、PN7和PN35时的心脏组织并提取mRNA。在心脏中，对于所有检测的基因，雄性存在年龄效应，PN1后表达下降。对于雌性，E20后JAK2表达显著降低，而雌性PI3K在E30和PN35时增加。此外，受限组中JAK/STAT信号靶点的mRNA表达以性别特异性方式显著改变。与对照组相比，在雄性中，受限组JAK2和STAT3显著降低，而在雌性中，受限后代中SOCS3显著增加，PI3K显著降低。最后，比较雄性和雌性时，JAK/STAT途径内基因表达水平存在特定差异。因此，生长受限改变了JAK/STAT信号通路中的特定靶点，JAK2和STAT3的改变可能导致生长受限男性心血管疾病风险增加。
