Hemodynamic regulation of blood-brain barrier phenotype: A cooperative effort linking adherens and tight junction complexes

Intercellular adherens junction (AJ) and tight junction (TJ) proteins (e.g. VE-Cadherin, occludin, ZO-1, claudin-5) jointly consolidate the apical surface of adjacent brain microvascular endothelial cells (BBMvEC’s) creating the blood-brain barrier (BBB), a critical regulator of CNS homeostasis. Junctional disassembly and barrier dysfunction are established features of cerebrovascular diseases (e.g. stroke) manifesting compromised blood flow, allowing us to hypothesize a pivotal regulatory link between BBB phenotype and flow-associated shear stress. In this regard, our research has demonstrated that exposure of BBMvEC’s to physiological levels of shear stress in vitro can upregulate tight junction protein expression and enhance protein immunolocalization at the cell-cell border, in parallel with reduced paracellular solute flux. \n\nFor these studies, cultured bovine brain microvascular endothelial cells (BBMvEC’s) were exposed to laminar shear stress (0-10 dynes/cm 2, 0-24 h) in conjunction with targeted inhibition strategies to delineate the intracellular signaling pathways mediating adaptation of BBB phenotype to fluid shear stress.\n\nInitial findings showed that shear-dependent reduction in BBMvEC permeability was initially observed after 3-6 h of shear onset (10 dynes/cm2), with more significant decreases observed after 12 and 24 h. These responses were temporally mirrored by BBMvEC morphological realignment, and were reversed by flow reduction (i.e. to 1 dynes/cm2, 24 h), the latter flow reduction also attenuated the enhanced cell-cell border localization of ZO-1 and reduction in phosphotyrosine (pTyr)-occludin levels induced by high shear.