title: Pulsatility and high shear stress deteriorate barrier phenotype in brain microvascular endothelium.
abstract: Microvascular endothelial cells at the blood-brain barrier exhibit a protective phenotype, which is highly induced by biochemical and biomechanical stimuli. Amongst them, shear stress enhances junctional tightness and limits transport at capillary-like levels. Abnormal flow patterns can reduce functional features of macrovascular endothelium. We now examine if this is true in brain microvascular endothelial cells. We suggest in this paper a complex response of endothelial cells to aberrant forces under different flow domains. Human brain microvascular endothelial cells were exposed to physiological or abnormal flow patterns. Physiologic shear (10-20 dyn/cm2) upregulates expression of tight junction markers Zona Occludens 1 (1.7-fold) and Claudin-5 (more than 2-fold). High shear stress (40 dyn/cm2) and/or pulsatility decreased their expression to basal levels and altered junctional morphology. We exposed cells to pathological shear stress patterns followed by capillary-like conditions. Results showed reversible recovery on the expression of tight junction markers. Flow protection of barrier phenotype commensurate with junctional signaling pathways decrease (Src, 0.25-fold, ERK, 0.77-fold) when compared to static conditions. This decrease was lost under high shear and pulsatile flow. In conclusion, abnormal shear stress inherent to systemic vascular disease leads to barrier impairment, which could be reverted by hemodynamic interventions.
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|2 IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Garcia-Polite
authors.affiliation: 2 IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Martorell
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|2 IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Del Rey-Puech
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar-Lesmes
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Caroline C
authors.initials: CC
authors.lastname: O'Brien
authors.affiliation: 3 Servei de Neurologia, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|4 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Roquer
authors.affiliation: 3 Servei de Neurologia, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|4 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: Ois
authors.affiliation: 3 Servei de Neurologia, Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain.|4 Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Principe
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|5 Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.affiliation: 1 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.|2 IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Balcells
mesh_terms: D001696:Biomechanical Phenomena; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000648:ultrastructure; D002199:Capillary Permeability; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D062507:Claudin-5 / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008856:Microscopy, Fluorescence; D055806:Microvessels / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D011673:Pulsatile Flow; D033081:Shear Strength; D013314:Stress, Mechanical; D019108:Tight Junctions / Q000378:metabolism* / Q000648:ultrastructure; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C107466:CLDN5 protein, human; D062507:Claudin-5; D017077:Culture Media, Conditioned; D062826:Zonula Occludens-1 Protein
keywords: Blood–brain barrier; capillaries; cerebrovascular disease; hemodynamics; microcirculation; neurovascular unit; vascular biology