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.

Debris-flow activity in abandoned channels of the Manival torrent reconstructed with LiDAR and tree-ring data

Hydrogeomorphic processes are a major threat in many parts of the Alps, where they periodically damage infrastructure, disrupt transportation corridors or even cause loss of life. Nonetheless, past torrential activity and the analysis of areas affected during particular events remain often imprecise. It was therefore the purpose of this study to reconstruct spatio-temporal patterns of past debris-flow activity in abandoned channels on the forested cone of the Manival torrent (Massif de la Chartreuse, French Prealps). A Light Detecting and Ranging (LiDAR) generated Digital Elevation Model (DEM) was used to identify five abandoned channels and related depositional forms (lobes, lateral levees) in the proximal alluvial fan of the torrent. A total of 156 Scots pine trees (Pinus sylvestris L.) with clear signs of debris flow events was analyzed and growth disturbances (GD) assessed, such as callus tissue, the onset of compression wood or abrupt growth suppression. In total, 375 GD were identified in the tree-ring samples, pointing to 13 debris-flow events for the period 1931–2008. While debris flows appear to be very common at Manival, they have only rarely propagated outside the main channel over the past 80 years. Furthermore, analysis of the spatial distribution of disturbed trees contributed to the identification of four patterns of debris-flow routing and led to the determination of three preferential breakout locations. Finally, the results of this study demonstrate that the temporal distribution of debris flows did not exhibit significant variations since the beginning of the 20th century.

European Working Group on Clinical Cell Analysis: Consensus protocol for the flow cytometric characterisation of platelet function

An increased or disturbed activation and aggregation of platelets plays a major role in the pathophysiology of thrombosis and haemostasis and is related to cardiovascular disease processes. In addition to qualitative disturbances of platelet function, changes in thrombopoiesis or an increased elimination of platelets, (e. g., in autoimmune thrombocytopenia), are also of major clinical relevance. Flow cytometry is increasingly used for the specific characterisation of phenotypic alterations of platelets which are related to cellular activation, haemostatic function and to maturation of precursor cells. These new techniques also allow the study of the in vitro response of platelets to stimuli and the modification thereof under platelet-targeted therapy as well as the characterisation of platelet-specific antibodies. In this protocol, specific flow cytometric techniques for platelet analysis are recommended based on a description of the current state of flow cytometric methodology. These recommendations are an attempt to promote the use of these new techniques which are at present broadly evaluated for diagnostic purposes. Furthermore, the definition of the still open questions primarily related to the technical details of the method should help to promote the multi-center evaluation of procedures with the goal to finally develop standardized operation procedures as the basis of interlaboratory reproducibility when applied to diagnostic testing.

Noninvasive pressure difference mapping derived from 4D flow MRI in patients with unrepaired and repaired aortic coarctation.

PURPOSE To develop a method for computing and visualizing pressure differences derived from time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and to compare pressure difference maps of patients with unrepaired and repaired aortic coarctation to young healthy volunteers. METHODS 4D flow MRI data of four patients with aortic coarctation either before or after repair (mean age 17 years, age range 3-28, one female, three males) and four young healthy volunteers without history of cardiovascular disease (mean age 24 years, age range 20-27, one female, three males) was acquired using a 1.5-T clinical MR scanner. Image analysis was performed with in-house developed image processing software. Relative pressures were computed based on the Navier-Stokes equation. RESULTS A standardized method for intuitive visualization of pressure difference maps was developed and successfully applied to all included patients and volunteers. Young healthy volunteers exhibited smooth and regular distribution of relative pressures in the thoracic aorta at mid systole with very similar distribution in all analyzed volunteers. Patients demonstrated disturbed pressures compared to volunteers. Changes included a pressure drop at the aortic isthmus in all patients, increased relative pressures in the aortic arch in patients with residual narrowing after repair, and increased relative pressures in the descending aorta in a patient after patch aortoplasty. CONCLUSIONS Pressure difference maps derived from 4D flow MRI can depict alterations of spatial pressure distribution in patients with repaired and unrepaired aortic coarctation. The technique might allow identifying pathophysiological conditions underlying complications after aortic coarctation repair.