1. Loss of Function in Heparan Sulfate Elongation Genes EXT1 and EXT 2 Results in Improved Nitric Oxide Bioavailability and Endothelial Function
- Author
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Mooij, HL, Cabrales, P, Bernelot Moens, SJ, Xu, D, Udayappan, SD, Tsai, AG, van der Sande, MAJ, de Groot, E, Intaglietta, M, Kastelein, JJP, Dallinga-Thie, GM, Esko, JD, Stroes, ES, and Nieuwdorp, M
- Subjects
Biomedical and Clinical Sciences ,Cardiovascular Medicine and Haematology ,Cardiovascular ,Adult ,Animals ,Brachial Artery ,Case-Control Studies ,Cell Line ,Endothelium ,Vascular ,Exostoses ,Multiple Hereditary ,Female ,Genetic Predisposition to Disease ,Glycocalyx ,Heterozygote ,Humans ,Male ,Mice ,Inbred C57BL ,Mice ,Knockout ,Middle Aged ,Mutation ,N-Acetylglucosaminyltransferases ,Nitric Oxide ,Nitric Oxide Synthase Type III ,Phenotype ,Phosphorylation ,Transfection ,Vasodilation ,endothelial function ,EXT ,heparan sulfate ,nitric oxide ,Cardiorespiratory Medicine and Haematology ,Cardiovascular medicine and haematology - Abstract
BackgroundHeparanase is the major enzyme involved in degradation of endothelial heparan sulfates, which is associated with impaired endothelial nitric oxide synthesis. However, the effect of heparan sulfate chain length in relation to endothelial function and nitric oxide availability has never been investigated. We studied the effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo.Methods and resultFlow-mediated dilation, a marker of nitric oxide bioavailability, was studied in Ext1(+/-) and Ext2(+/-) mice versus controls (n=7 per group), as well as in human subjects with heterozygous loss of function mutations in EXT1 and EXT2 (n=13 hereditary multiple exostoses and n=13 controls). Endothelial function was measured in microvascular endothelial cells under laminar flow with or without siRNA targeting EXT1 or EXT2. Endothelial glycocalyx and maximal arteriolar dilatation were significantly altered in Ext1(+/-) and Ext2(+/-) mice compared to wild-type littermates (glycocalyx: wild-type 0.67±0.1 μm, Ext1(+/-) 0.28±0.1 μm and Ext2(+/-) 0.25±0.1 μm, P
- Published
- 2014