Adaptive and maladaptive endothelial cell dynamics during blood flow-driven vascular patterning

ended

The formation of a functional patterned (adaptation) vascular network is essential for development, tissue growth, and organ physiology. Several human vascular disorders arise from the mis-patterning (maladaptation) of blood vessels, such as arteriovenous malformations, aneurysms, and diabetic retinopathy. Blood flow is recognized as the main inducer for vascular patterning, yet very little is known about the molecular mechanisms that vascular patterning. C. Franco and others recently highlighted that endothelial cells polarize and migrate against the blood flow direction. Yet, how this behavior contributes to the overall process of vascular patterning is completely unknown. This project aims to study the dynamics of endothelial cells in vascular patterning during development, homeostasis, and disease. Taking advantage of a unique new transgenic mouse line reporting endothelial cell polarity in vivo, I will investigate endothelial cell behavior in vivo, including endothelial cell polarity, collective and individual migration and cell rearrangements, using 2-photon microscopy. I will extend this analysis to understand the involvement of endothelial flow-dependent polarity in formation and development of arteriovenous malformations. Finally, I will perform an in vivo functional screen to identify novel regulators of endothelial flow-dependent polarity, using a combination of automated image analysis and hemodynamics modelling. This integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in adaptive and maladaptive endothelial cell dynamics during blood flow-driven vascular patterning. Given the physiological relevance of vascular patterning in health and disease, this research plan will set the basis for the development of novel clinical therapies targeting vascular disorders.