Control of protein trafficking in vascular physiology and pathology

The blood vascular network is a branched system irrigating all organs in vertebrates, which is fundamental for embryogenesis, physiology and healing. Dysfunction of this network is associated with multiple diseases, including cancer progression, diabetic retinopathies, or arteriovenous malformations. The majority of blood vessels form through angiogenesis, which is driven by endothelial cells (ECs), the cells lining the interior of blood vessels. In both physiological and pathological scenarios, angiogenesis involves a series of steps that rely on EC migration, proliferation and specialization. Recent advances by us and others highlighted an important feature of ECs in response to the physical force (wall shear stress) exerted by blood: in response to flow ECs polarize (front-rear polarity) and migrate against the blood flow direction, which we define as EC flow-migration coupling.EC polarity and migration regulates vessel architecture and specialization and its dysfunction contributes to disease, notably to arteriovenous malformations and atherosclerosis. Yet, despite it’s the correlation between dysfunctional EC flow-migration coupling with pathology, the mechanistic consequences of impaired EC flow-migration coupling remain poorly understood. Alongside, polarized secretion has been long identified as an essential EC function. It controls barrier function and molecular exchanges between blood and tissues, and enables communication with extravascular cells through localized secretion of angiocrine factors. This polarized secretion is thought to contribute to vascular stabilization and homeostasis. However, the mechanisms governing polarised secretion remain to be elucidated. Moreover, the effects of blood flow on polarized secretion remains unexplored. Thus, based on our current understanding of EC biology, we propose the novel hypothesis that EC flow-migration coupling regulates polarized secretion.