ArticleJournal of the American Heart Association2014
Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function.
Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
- Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial.Journal of translational medicine · 2021Trial
- Heparan sulfate as a central modulator of growth factor dynamics in tissue regeneration.APL bioengineering · 2025Article
- Evaluation of Endothelial Glycocalyx Damage in Neonatal Lambs With Diarrhoea: A Biomarker-Based Approach.Veterinary medicine and science · 2025Article
- A novel role of exostosin glycosyltransferase 2 (EXT2) in glioblastoma cell metabolism, radiosensitivity and ferroptosis.Cell death and differentiation · 2025Article
- Endothelial glycocalyx in hepatopulmonary syndrome: An indispensable player mediating vascular changes.Frontiers in immunology · 2022Review
- The effectiveness of alprostadil in treating coronary microcirculation dysfunction following ST-segment elevation myocardial infarction in a pig model.Experimental and therapeutic medicine · 2021Article
- Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses.Molecular genetics and metabolism reports · 2021Article
- Loss of Hs3st3a1 or Hs3st3b1 enzymes alters heparan sulfate to reduce epithelial morphogenesis and adult salivary gland function.Matrix biology : journal of the International Society for Matrix Biology · 2021Article
- Protectin conjugates in tissue regeneration 1 restores lipopolysaccharide-induced pulmonary endothelial glycocalyx loss via ALX/SIRT1/NF-kappa B axis.Respiratory research · 2021Article
- Transportan Peptide Stimulates the Nanomaterial Internalization into Mammalian Cells in the Bystander Manner through Macropinocytosis.Pharmaceutics · 2021Article
- Transcapillary escape rate ofEJNMMI radiopharmacy and chemistry · 2021Article
- Syndecan receptors: pericellular regulators in development and inflammatory disease.Open biology · 2021Review
- Microvascular thrombosis: experimental and clinical implications.Translational research : the journal of laboratory and clinical medicine · 2020Review
- Stress-induced RNA-chromatin interactions promote endothelial dysfunction.Nature communications · 2020Article
- Abnormal sodium and water homeostasis in mice with defective heparan sulfate polymerization.PloS one · 2019Article
- Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance.PloS one · 2018Article
- Genome-wide admixture and association study of subclinical atherosclerosis in the Women's Interagency HIV Study (WIHS).PloS one · 2017Article
- Hereditary Multiple Exostoses: a review of clinical appearance and metabolic pattern.Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal DiseasesReview
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Authors and funding
14 authors at 3 institutions in 2 countries.
Funding
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<0.01, maximal arteriolar dilation during reperfusion: wild-type 11.3±1.0%), Ext1(+/-) 15.2±1.4% and Ext2(+/-) 13.8±1.6% P<0.05). In humans, brachial artery flow-mediated dilation was significantly increased in hereditary multiple exostoses patients (hereditary multiple exostoses 8.1±0.8% versus control 5.6±0.7%, P<0.05). In line, silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression.
conclusionsOur data implicate that heparan sulfate elongation genes EXT1 and EXT2 are involved in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability.
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