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Heparan sulfates mediate pressure-induced increase in lung endothelial hydraulic conductivity via nitric oxide/reactive oxygen species

¹Department of Anesthesiology, Lung Vascular Biology Laboratory, ²Department of Bioengineering, and ³Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, School of Medicine, Salt Lake City, Utah

Submitted 22 September 2006 ; accepted in final form 27 February 2007

We investigated the nonlinear dynamics of the pressure vs. hydraulic conductivity (L_p) relationship in lung microvascular endothelial cells and demonstrate that heparan sulfates, an important component of the endothelial glycocalyx, participate in pressure-sensitive mechanotransduction that results in barrier dysfunction. The pressure vs. L_p relationship was complex, possessing both time- and pressure-dependent components. Pretreatment of lung capillary endothelial cells with heparanase III completely abolished the pressure-induced increase in L_p. This extends our (7) previous observation regarding heparan sulfates as mechanotransducers for shear stress. Inhibition of nitric oxide (NO) synthase with L-NAME (N^G-nitro-L-arginine methyl ester HCl) and intracellular scavenging of reactive oxygen species (ROS) by TBAP [tetrakis-(4-benzoic acid) porphorin] significantly attenuated the pressure-induced L_p response. Intracellular NO/ROS were visualized using the fluorescent dye, 2'7'-dichlorofluorescein diacetate (DCFA), and cells demonstrated a pressure-induced increase in intracellular fluorescence. Heparanase pretreatment significantly reduced the pressure-induced increase in intracellular fluorescence, suggesting that cell-surface heparan sulfates directly participate in mechanotransduction that results in NO/ROS production and increased permeability. This is the first report to demonstrate a role for heparan sulfates in pressure-mediated mechanotransduction and barrier regulation. These observations may have important clinical implications during conditions where pulmonary microvascular pressure is elevated.

glycocalyx; mechanotransduction

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