Arteriosclerosis, thrombosis, and vascular biology
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Arterioscler. Thromb. Vasc. Biol. · Aug 2018
Hypoalphalipoproteinemia and BRAFV600E Mutation Are Major Predictors of Aortic Infiltration in the Erdheim-Chester Disease.
Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. ⋯ Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.
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Arterioscler. Thromb. Vasc. Biol. · Aug 2018
BMP9 (Bone Morphogenetic Protein-9)/Alk1 (Activin-Like Kinase Receptor Type I) Signaling Prevents Hyperglycemia-Induced Vascular Permeability.
Objective- Diabetic macular edema is a major cause of visual impairment. It is caused by blood-retinal barrier breakdown that leads to vascular hyperpermeability. Current therapeutic approaches consist of retinal photocoagulation or targeting VEGF (vascular endothelial growth factor) to limit vascular leakage. ⋯ Conversely, sustained delivery of BMP9 by adenoviral vectors significantly decreased the loss of retinal barrier function in diabetic mice. Mechanistically, we demonstrate that Alk1 signaling prevents VEGF-induced phosphorylation of VE-cadherin and induces the expression of occludin, thus strengthening vascular barrier functions. Conclusions- From these data, we suggest that by preventing retinal vascular permeability, BMP9 could serve as a novel therapeutic agent for diabetic macular edema.