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Am J Physiol Lung Cell Mol Physiol (March 9, 2007). doi:10.1152/ajplung.00376.2006
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Submitted on September 22, 2006
Accepted on February 27, 2007

Heparan Sulfates Mediate Pressure-Induced Increase In Lung Endothelial Hydraulic Conductivity via NO/ROS

Randal O. Dull1*, Ian Mecham2, and Scott McJames3

1 Anesthesiology, University of Utah, Salt Lake City, Utah, United States; Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States; Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah, United States
2 Anesthesiology, University of Utah, Salt Lake City, Utah, United States; Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States
3 Anesthesiology, University of Utah, Salt Lake City, Utah, United States

* To whom correspondence should be addressed. E-mail: randal.dull{at}hsc.utah.edu.

We investigated the non-linear 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 mechano-transduction 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 previous observation regarding heparan sulfates as mechano-transducers for shear stress (7). Inhibition of nitric oxide synthase with L-NAME and intracellular scavenging of reactive oxygen species (ROS) by TBAP significantly attenuated the pressure-induced Lp response. Intracellular NO/ROS were visualized using the fluorescent dye, 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 mechano-transduction that results in NO/ROS production and increased permeability. This is the first report to demonstrate a role for heparan sulfates in pressure-mediated mechano-transduction and barrier regulation. These observations may have important clinical implications during conditions where pulmonary microvascular pressure is elevated.




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