Scott Kayley, Morgan Hannah L, Delles Christian, Fisher Simon, Graham Delyth, McBride Martin W
British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Scotland, United Kingdom.
Physiol Genomics. 2021 Apr 1;53(4):160-171. doi: 10.1152/physiolgenomics.00159.2020. Epub 2021 Mar 15.
During pregnancy, the uterine spiral arteries undergo major vascular remodeling to ensure sufficient uteroplacental perfusion to support the fetus. In pregnancies complicated by hypertensive disorders, this remodeling is deficient leading to impaired uteroplacental blood flow and poor maternal and fetal outcomes. The underlying genetic mechanisms for failed vascular remodeling are not fully understood. This study aimed to examine the early-pregnancy-associated gene changes in the uterine arteries of spontaneously hypertensive stroke-prone rats (SHRSP) compared with their normotensive counterparts, Wistar-Kyoto rats (WKY). Uterine arteries from WKY and SHRSP were processed for RNA-sequencing, along with virgin, age-matched controls for each strain. Gene expression changes were identified and biological pathways were implicated and interpretated using ingenuity pathway analysis (IPA). This study found that WKY uterine arteries from early pregnancy exhibit a gene expression pattern that is suggestive of a pregnancy-dependent reduction in Ca handling and renin-angiotensin-aldosterone system (RAAS) components and an increase in ATP production. In contrast, the expression pattern of pregnant SHRSP uterine arteries was dominated by an elevated immune response and increased production of reactive oxygen species (ROS) and downstream effectors of the RAAS. These results suggest that in a rat model, hypertension during pregnancy impacts uterine artery gene expression patterns as early as the first week of pregnancy. The pathway changes involved may underlie or contribute to the adverse vascular remodeling and resultant placental ischemia and systemic vascular dysfunction observed in SHRSP in late gestation.
在孕期，子宫螺旋动脉会经历重大的血管重塑，以确保充足的子宫胎盘灌注来支持胎儿。在并发高血压疾病的妊娠中，这种重塑存在缺陷，导致子宫胎盘血流受损，母婴结局不良。血管重塑失败的潜在遗传机制尚未完全明确。本研究旨在比较自发性高血压易中风大鼠（SHRSP）与其正常血压对照Wistar-Kyoto大鼠（WKY）在妊娠早期子宫动脉中与妊娠相关的基因变化。对WKY和SHRSP的子宫动脉进行RNA测序，并设置每个品系的未孕、年龄匹配的对照。使用 Ingenuity 通路分析（IPA）来识别基因表达变化，并阐明和解释生物学通路。本研究发现，妊娠早期WKY的子宫动脉呈现出一种基因表达模式，提示与妊娠相关的钙处理及肾素-血管紧张素-醛固酮系统（RAAS）成分减少，以及ATP生成增加。相比之下，妊娠SHRSP子宫动脉的表达模式以免疫反应增强、活性氧（ROS）生成增加以及RAAS的下游效应物增加为主。这些结果表明，在大鼠模型中，孕期高血压早在妊娠第一周就会影响子宫动脉基因表达模式。所涉及的通路变化可能是妊娠晚期SHRSP中观察到的不良血管重塑以及由此导致的胎盘缺血和全身血管功能障碍的基础或促成因素。
