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

Randal O. Dull, Ian Mecham, Scott McJames

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

We investigated the nonlinear dynamics of the pressure vs. hydraulic conductivity (Lp) 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. Lp 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 Lp. 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 pressureinduced Lp 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 cellsurface 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.

Original languageEnglish (US)
Pages (from-to)L1452-L1458
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number6
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • Glycocalyx
  • Mechanotransduction

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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