FOXC2 and fluid shear stress stabilize postnatal lymphatic vasculature

Biomechanical forces, such as fluid shear stress, govern multiple aspects of endothelial cell biology. In blood vessels, disturbed flow is associated with vascular diseases, such as atherosclerosis, and promotes endothelial cell proliferation and apoptosis. Here, we identified an important role for disturbed flow in lymphatic vessels, in which it cooperates with the transcription factor FOXC2 to ensure lifelong stability of the lymphatic vasculature. In cultured lymphatic endothelial cells, FOXC2 inactivation conferred abnormal shear stress sensing, promoting junction disassembly and entry into the cell cycle. Loss of FOXC2-dependent quiescence was mediated by the Hippo pathway transcriptional coactivator TAZ and, ultimately, led to cell death. In murine models, inducible deletion of Foxc2 within the lymphatic vasculature led to cell-cell junction defects, regression of valves, and focal vascular lumen collapse, which triggered generalized lymphatic vascular dysfunction and lethality. Together, our work describes a fundamental mechanism by which FOXC2 and oscillatory shear stress maintain lymphatic endothelial cell quiescence through intercellular junction and cytoskeleton stabilization and provides an essential link between biomechanical forces and endothelial cell identity that is necessary for postnatal vessel homeostasis. As FOXC2 is mutated in lymphedema-distichiasis syndrome, our data also underscore the role of impaired mechanotransduction in the pathology of this hereditary human disease.

Comparisons between analogue and numerical models of thrust wedge development

Analogue and finite element numerical models with frictional and viscous properties are used to model thrust wedge development. Comparison between model types yields valuable information about analogue model evolution, scaling laws and the relative strengths and limitations of the techniques. Both model types show a marked contrast in structural style between ‘frictional-viscous domains’ underlain by a thin viscous layer and purely ‘frictional domains’. Closely spaced thrusts form a narrow and highly asymmetric fold-and-thrust belt in the frictional domain, characterized by in-sequence propagation of forward thrusts. In contrast, the frictional-viscous domain shows a wide and low taper wedge and a thrust belt with a more symmetrical vergence, with both forward and back thrusts. The frictional-viscous domain numerical models show that the viscous layer initially simple shears as deformation propagates along it, while localized deformation resulting in the formation of a pop-up structure occurs in the overlying frictional layers. In both domains, thrust shear zones in the numerical model are generally steeper than the equivalent faults in the analogue model, because the finite element code uses a non-associated plasticity flow law. Nevertheless, the qualitative agreement between analogue and numerical models is encouraging. It shows that the continuum approximation used in numerical models can be used to model frictional materials, such as sand, provided caution is taken to properly scale the experiments, and some of the limitations are taken into account.