Shear stress-mediated vascular survival in the brain

• Applicant: Dr. Jan Wenzel
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Anatomy and Physiology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456052613

The aim of the project is to decipher new mechanisms by which the vasculature in the brain maintains its function with a focus on the role of endothelial cells (ECs) in the smallest vessels, capillaries. ECs of the vasculature are in direct contact with hemodynamic forces that are induced by blood components and flow patterns, called shear stress. Capillaries are characterized by a diameter that is smaller than the diameter of an erythrocyte that is passing through. Therefore, each flowing blood cell induces shear stress and this flow-through is irregular and heterogeneous, and could even reverse its direction, as shown for brain capillaries. Since capillaries are currently discussed to be the main source of vascular resistance in the brain, the response to shear stress at this level of the vascular tree seems to be vital for the maintenance of stable blood perfusion in the brain.The mechanisms of sensing mechanical forces at ECs have been a focus of recent vascular research due to endothelial alterations that occur during diseases like atherosclerosis. These alterations are mainly located in areas that are exposed to disturbed or oscillatory shear stress. The main part of this research has dealt with big vessels that, when dysfunctional, deposit atherosclerotic plaques and develop stenosis. How smaller vessels are affected by endothelial dysfunction and disturbed flow patterns is so far underexamined but could be similarly important, especially in the brain. Small vessels form by far the largest vascular surface and are involved in organ function as they present the main location of gas and nutrient exchange. Moreover, the occurrence of microinfarcts due to small vessel occlusion are causative for cognitive impairment. Finally, small vessel diseases are one of the main causes of dementia.The overarching goal of this project is to find new mechanisms by which shear stress affects vascular pathology in the brain, with a special focus on capillary ECs. We will investigate endothelial sensor proteins and signalling mechanisms to decipher the effects of altered shear stress on death and survival of the microvasculature of the brain. According to our hypothesis, endothelial sensing of non-laminar shear stress in capillaries protects the brain vasculature and thereby prevents secondary vascular dementia. By applying different in vitro and in vivo techniques that we have developed in the past we will work on different objectives and describe and manipulate shear stress responses in the brain.The expected findings will have a strong impact on the understanding of the development of microvascular damages in the brain and their subsequent effects on cognition. Since small vessels are affected by several diseases such as diabetes or hypertension, the results of the project could have direct implications not only for patients that suffer from neurological but also peripheral diseases with indirect effects on the vasculature.

• DFG Programme: Research Grants