Sexually dimorphic regulation of vascular tone by signaling cross-talk of bioactive lipids

点击翻译按钮获取中文摘要

My group studies factors that cause arteries to become narrower (constricted) versus how they become wider (relaxed). The balance of these opposite responses controls blood pressure. We study two factors called LPA and S1P, which often have similar effects on arteries. However, there are also differences and unique actions of LPA versus S1P. Most researchers study LPA and S1P separately. This misses a critical level of control because each of these factors affects the other. Thus, the responses to LPA and S1P are tightly linked and should be studied together, especially since these interactions differ between men and women. LPA and S1P in the blood interact with cells that line arteries. This sends signals to the underlying muscle cells to relax, which decreases blood pressure. However, when S1P levels rise, the artery lining becomes leaky and allows LPA and S1P in the blood to gain access to the underlying muscle layer. Here, LPA and S1P offset the relaxation by making the muscle constrict, which increases blood pressure. We will study how LPA and S1P work together to control these opposing effects. This is vital to understanding the control of normal blood pressure. Once we understand how normal responses are controlled, we can then begin to discover changes that lead to diseases. We have novel evidence that LPA and S1P are controlled by a factor called SPH, which is also present in the blood. SPH enters cells where it is used to make S1P, which goes back into the blood to control relaxation. We now show that SPH has other effects, one of which is to control the actions of LPA. In turn, LPA controls S1P production. Significantly, SPH levels in blood are about 10 times higher in females compared to males, probably because of the actions of estrogen. The effect of SPH in directing the actions of LPA versus S1P has never been studied. We do not know how this will control artery function in health or in disease and if there will be differences in men and pre- and post-menopausal women. Our proposal will fill these gaps in knowledge. We will study how SPH coordinates the relative effects of LPA and S1P and how this differs between the sexes. My work focuses on understanding how women and men use LPA and S1P to control the function of arteries at different stages of their lives. Understanding these normal responses will also help us to explain why the signs and symptoms of diseases involving the arteries are so different in men and women. Importantly, we will define the normal ways in which SPH, LPA and S1P control responses in arteries and why it is critical to take into account the different responses in women and men. Knowledge from our studies can be applied to tissues other than arteries since LPA and S1P are essential factors in a broad range of responses. Our results should identify new opportunities for the pharmaceutical industry in Canada to develop therapies to treat high blood pressure and heart attacks.