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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:35.)
© 2000 American Heart Association, Inc.

Vascular Biology

Shear-Induced Increase in Hydraulic Conductivity in Endothelial Cells Is Mediated by a Nitric Oxide–Dependent Mechanism

Yong S. Chang; Jean Ann Yaccino; Sunitha Lakshminarayanan; John A. Frangos; John M. Tarbell

From the Departments of Physiology (Y.S.C., J.A.Y.) and Chemical Engineering (S.L., J.M.T.), Biomolecular Transport Dynamics Laboratory, The Pennsylvania State University, University Park, Pa, and the Department of Bioengineering (J.A.F.), University of California, San Diego, La Jolla, Calif.

Correspondence to Dr John M. Tarbell, 155 Fenske Laboratory, Department of Chemical Engineering, The Pennsylvania State University, University Park, PA 16802. E-mail jmt{at}psu.edu

Abstract—This study addresses the role of nitric oxide (NO) and its downstream mechanism in mediating the shear-induced increase in hydraulic conductivity (L_p) of bovine aortic endothelial cell monolayers grown on porous polycarbonate filters. Direct exposure of endothelial monolayers to 20-dyne/cm² shear stress induced a 4.70±0.20-fold increase in L_p at the end of 3 hours. Shear stress (20 dyne/cm²) also elicited a multiphasic NO production pattern in which a rapid initial production was followed by a less rapid, sustained production. In the absence of shear stress, an exogenous NO donor, S-nitroso-N-acetylpenicillamine, increased endothelial L_p 2.23±0.14-fold (100 µmol/L) and 4.8±0.66-fold (500 µmol/L) at the end of 3 hours. In separate experiments, bovine aortic endothelial cells exposed to NO synthase inhibitors, N^G-monomethyl-L-arginine and N^G-nitro-L-arginine methyl ester, exhibited significant attenuation of shear-induced increase in L_p in a dose-dependent manner. Inhibition of guanylate cyclase (GC) with LY-83,583 (1 µmol/L) or protein kinase G (PKG) with KT5823 (1 µmol/L) failed to attenuate the shear-induced increase in L_p. Furthermore, direct addition of a stable cGMP analogue, 8-bromo-cGMP, had no effect in altering baseline L_p, indicating that the GC/cGMP/PKG pathway is not involved in shear stress–NO–L_p response. Incubation with iodoacetate (IAA), a putative inhibitor of glycolysis, dose-dependently increased L_p. Addition of IAA at levels that did not affect baseline L_p greatly potentiated the response of L_p to 20-dyne/cm² shear stress. Finally, both shear stress–induced and IAA-induced increases in L_p could be reversed with the addition of dibutyryl cAMP. However, additional metabolic inhibitors, 2 deoxyglucose (10 mmol/L) and oligomycin (1 µmol/L), or reactive oxygen species scavengers, deferoxamine (1 mmol/L) and ascorbate (10 mmol/L), failed to alter shear-induced increases in L_p. Our results show that neither the NO/cGMP/PKG pathway nor a metabolic pathway mediates the shear stress–L_p response. An alternate mechanism downstream from NO that is sensitive to IAA must mediate this response.

Key Words: shear stress • nitric oxide • hydraulic conductivity • endothelial cells

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