Mechanoregulation of Jagged in Vascular Tissue Homeostasis

Cardiovascular diseases are among the major causes of death worldwide, and typically arise as a result of intrinsic factors (e.g.mutations) or adverse changes in tissue composition and architecture. Although it is widely accepted that the growth and remodelingcapacity of cardiovascular tissues plays a fundamental role in the maintenance and disruption of tissue functionality, a mechanistic understanding of the underlying mechanisms is still missing Mechanical stresses induced by blood flow and Notch signaling are both known to regulate vascular tissue form and function. Jagged-Notch signalling plays a major role in regulating tissue composition and architecture. On the other hand, the mechanical state of the tissue has been hypothesized to drive tissue remodeling towards a preferred mechanical homeostasis. Both phenomena may be interlinked via the mechanosensitivity of Jagged-Notch signaling . Understanding the complex interactions between cell-cell signaling and mechanics is therefore essential for obtaining a mechanistic understanding of the processes responsible for the regulation of vascular tissue development and homeostasis. The main hypothesis of this project is that the hemodynamic environment critically influences vascular tissue physiology and pathology through interaction with the Notch signaling pathway. We envision that detailed and mechanistic understanding of the interrelationship between Notch signaling and mechanics will open up new therapeutic possibilities and help us predict therapeutic outcomes in vascular medicine and engineering. We will use an interdisciplinary research approach and novel model systems to address our objectives. By integrating molecular cell biology and in vivo model systems with microtissue engineering and computational modelling, we aim to gain mechanistic insight of how cell signalling and hemodynamic forces integrate in vascular tissue.