How genetic variants of von Willebrand factor with altered force responsiveness elevate the risk of vascular disease

• Applicant: Privatdozentin Dr. Maria Alexandra Brehm
• Subject Area: Cell Biology ; Biochemistry
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 432690106

Myocardial infarction (MI) and stroke are among the most common causes of death. To fight these diseases, it is of utmost importance to understand their underlying causes as a basis for the development of new and more effective treatment and prevention options. To date, research efforts are focused mainly on the distinct characteristics specific for each single disease of interest. This project envisions a novel approach based on the fact that the above-mentioned conditions share the following principle:Development and progression of vascular diseases are critically regulated and affected by the response of the vasculature and blood components to mechanical forces.In blood vessels, the endothelium resides in a unique biomechanical stress environment because blood is flowing (hemodynamics). Thus, endothelial cells (EC’s) constantly sense the magnitude and directionality of this hydrodynamic force and the resulting wall shear stress, and transduce this mechanical signal into biochemical signals that regulate cellular function. In the event of vascular injury, hemodynamics is altered and EC’s react to the increase in hydrodynamic force by adjusting transcription and protein secretion. One of the proteins released upon this activation is the glycoprotein von Willebrand factor (VWF), which subsequently is force-activated to recruit platelets to the site of injury. In disease, EC activation and platelet recruitment are initiated in the absence of injury. The result can be thrombosis, MI or stroke. VWF is a prototype of a force-regulated protein and it has been suggested that VWF is involved in thromboembolic events. For five genetic VWF variants, we have indeed shown that their force responsiveness is altered. For two of them, we identified two different mechanisms: a) lowering of the force threshold required for activation, and b) stronger activation by the same force as required for wildtype VWF activation. These alterations are putative novel risk factors for myocardial infarction (MI). The characterization of the mechanisms leading to alterations in the force responsiveness of the other three variants is one main objective of this proposal.The overall goal of this project is to elucidate how VWF regulates the relationship between vascular biology, hemodynamics and vascular disease. The results will be used to identify novel intervention points that can be targeted by directly blocking the activation of these flow-induced disease pathways. Research objectives are: 1) determine the mechanisms of increased VWF force responsiveness by elucidating the mechanobiological properties of VWF variants employing biophysical, biochemical and cell biological approaches as well as mouse models, 2) identify components with the capability to inhibit VWF hypermechanosensitivity to develop new treatment and prevention options for vascular disease, and 3) characterize the clinical relevance of VWF force responsiveness in vascular disease.

• DFG Programme: Research Grants