title: Glycocalyx Degradation Induces a Proinflammatory Phenotype and Increased Leukocyte Adhesion in Cultured Endothelial Cells under Flow.
abstract: Leukocyte adhesion to the endothelium is an early step in the pathogenesis of atherosclerosis. Effective adhesion requires the binding of leukocytes to their cognate receptors on the surface of endothelial cells. The glycocalyx covers the surface of endothelial cells and is important in the mechanotransduction of shear stress. This study aimed to identify the molecular mechanisms underlying the role of the glycocalyx in leukocyte adhesion under flow. We performed experiments using 3-D cell culture models, exposing human abdominal aortic endothelial cells to steady laminar shear stress (10 dynes/cm2 for 24 hours). We found that with the enzymatic degradation of the glycocalyx, endothelial cells developed a proinflammatory phenotype when exposed to uniform steady shear stress leading to an increase in leukocyte adhesion. Our results show an up-regulation of ICAM-1 with degradation compared to non-degraded controls (3-fold increase, p<0.05) and we attribute this effect to a de-regulation in NF-κB activity in response to flow. These results suggest that the glycocalyx is not solely a physical barrier to adhesion but rather plays an important role in governing the phenotype of endothelial cells, a key determinant in leukocyte adhesion. We provide evidence for how the destabilization of this structure may be an early and defining feature in the initiation of atherosclerosis.
authors.affiliation: Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.
authors.forename: Karli K
authors.initials: KK
authors.lastname: McDonald
authors.affiliation: Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Cooper
authors.affiliation: Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada.
authors.forename: Lisa
authors.initials: L
authors.lastname: Danielzak
authors.affiliation: Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada.|Department of Chemical Engineering, McGill University, Montreal, Quebec, Canada.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Leask
mesh_terms: D001696:Biomechanical Phenomena; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002460:Cell Line; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D019276:Glycocalyx / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D040542:Mechanotransduction, Cellular; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D012212:Rheology; D013314:Stress, Mechanical
chemical_list: C573420:ICAM1 protein, human; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III