Hypertension is estimated to cause 7.6 million premature deaths worldwide each year - about 13.5% of the total number of all deaths. Hypertension is a chronic condition that contributes to the development of numerous cardiovascular diseases, including heart failure, vascular dementia, and stroke. While increased blood pressure levels are related to increasing cardiovascular risk, the precise mechanisms that lead from hypertension to ill health are poorly understood.
The adverse effects of hypertension are mediated by changes in the structure and function of the artery wall. A key contributor to the changes that occur in the artery wall is dysfunction in the innermost layer of cells in blood vessels known as the endothelium. The endothelium is a pivotal regulator of vascular tone, cell proliferation, blood clotting and immune responses. Dysfunction in the endothelium underlies the debilitating vascular changes that accompany hypertension and atherosclerosis.
The endothelium operates normally by converting various extracellular stimuli to specific vascular functions through changes in endothelial cytosolic Ca2+ concentration. However, despite the importance of endothelial Ca2+ signaling to the control of vascular function there is surprisingly little known in the changes that occur in hypertension. We found that vascular contractility was increased in hypertension, and that this was caused by impaired endothelial Ca2+ signalling; basal endothelial Ca2+ activity limits vascular contraction, but that Ca2+-dependent control is impaired in hypertension.
Projections between endothelial and smooth muscle cells (MEPs) contain several Ca2+-dependent effector proteins and act as a functional hub where endothelial signaling pathways merge to promote relaxation of smooth muscle cells. We were able to show two changes in IP3-mediated Ca2+ signals at MEPs that explain the impaired endothelial control of vascular smooth muscle contraction. First, there is a reduced liberation of Ca2+ from active Ca2+ release sites, which are positioned near MEPs. Second, there is decoupling of active Ca2+ release sites and MEPs, and an increased distance between them. Together, these alterations to myoendothelial Ca2+ signaling dynamics decrease endothelial control of vascular smooth muscle contraction and explain the increased smooth muscle cell contractility that is characteristic of hypertension.
Our main focus is now to try and understand how an interactive signalling web that we have identified, and which extends across many cells in the endothelium, communicates and coordinates vascular function. We are also working to determine how this signaling web is disrupted to contribute to the development of hypertension. We have found that cells in the endothelium are not all alike but are specialized to detect specific types of signals. The endothelium uses these specialized cells to manage the large quantity of information that is continuously present in the body and which undergoes constant change (see the Signalling Network section for more information). These specialized cells communicate with each other by the endothelial network. Cell network communications and interactions are essential for normal vascular function to occur and, when these network communications change, vascular disease occurs. We have seen, for example, that this network is disrupted in vascular disease, where altered cell heterogeneity and arrangement decreases endothelial function. The network offers a new framework for understanding how compromised endothelial function leads to cardiovascular disease and hypertension.
We are now asking the following questions:
What features of the endothelial network that are compromised in hypertension may be used to generate new therapies?
Why, and how, are the communication mechanisms used by the endothelium altered in hypertension?
Precisely how are specific network communications linked to particular normal functions and what targets do they present to control hypertension?
Using new advanced imaging methods that we have developed to visualize the endothelium we are, for the first time, seeing the new blood vessel problems in hypertension and we are establishing targets for therapeutic drug development.
Lab members working on hypertension:
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