Optogenetic control of vascular function during pregnancy

点击翻译按钮获取中文摘要

Intrauterine growth restriction (IUGR) increases the risk of stillbirth and neonatal death. The adverse effects of being born IUGR extend well beyond the perinatal period, increasing the risk of cardiovascular disease, among others, in later life. Impaired vascular adaptation to pregnancy is a predominant contributor to IUGR. To understand the effects of impaired uterine vasculature on maternal and infant health, we propose using optogenetics technology for manipulating uterine blood flow in live animals. Optogenetics is an innovative technique in which genetically modified cells express light-activated microbial opsins (e.g., channelrhodopsin- 2, ChR2), which can then be selectively stimulated by light in vivo. Our goal is to develop a novel, reliable and physiologically relevant murine model of IUGR using optogenetics. To address this goal, we propose to conduct two integrated scientific aims. In Aim 1, we will determine the effect of in vitro light stimulation on uterine artery function in pregnant smooth muscle specific ChR2 transgenic mice. Aim 2 will address the capacity for light stimulation to constrict the uterine artery in vivo, reducing uterine artery blood flow and producing IUGR. Current murine models for reducing uterine blood flow require uterine artery ligations, which have undesirable consequences such as high rate of fetal death and low reproducibility. Our optogenetic IUGR model will provide better control of the degree of blood flow manipulation, enhanced reproducibility among experiments, improved selectivity of the stimulation, and reduced fetal mortality. This project will be the first to apply optogenetics to the study of uterine vascular function in vivo. Importantly, our proposal can provide the foundation for applying optogenetics to the study of other vascular beds in vivo.