Lung heparan sulfates modulate Kfc during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction

Dull RO, Cluff M, Kingston J, Hill D, Chen H, Hoehne S, Malleske DT, Kaur R. Lung heparan sulfates modulate K-fc during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction. Am J Physiol Lung Cell Mol Physiol 302: L816-L828, 2012. First published December 9, 2011; doi: 10.1152/ajplung.00080.2011.-Lung endothelial cells respond to changes in vascular pressure through mechanotransduction pathways that alter barrier function via non-Starling mechanism(s). Components of the endothelial glycocalyx have been shown to participate in mechanotransduction in vitro and in systemic vessels, but the glycocalyx's role in mechanosensing and pulmonary barrier function has not been characterized. Mechanotransduction pathways may represent novel targets for therapeutic intervention during states of elevated pulmonary pressure such as acute heart failure, fluid overload, and mechanical ventilation. Our objective was to assess the effects of increasing vascular pressure on whole lung filtration coefficient (K-fc) and characterize the role of endothelial heparan sulfates in mediating mechanotransduction and associated increases in K-fc. Isolated perfused rat lung preparation was used to measure K-fc in response to changes in vascular pressure in combination with superimposed changes in airway pressure. The roles of heparan sulfates, nitric oxide, and reactive oxygen species were investigated. Increases in capillary pressure altered K-fc in a nonlinear relationship, suggesting non-Starling mechanism(s). nitro-L-arginine methyl ester and heparanase III attenuated the effects of increased capillary pressure on K-fc, demonstrating active mechanotransduction leading to barrier dysfunction. The nitric oxide (NO) donor S-nitrosoglutathione exacerbated pressure-mediated increase in K-fc. Ventilation strategies altered lung NO concentration and the K-fc response to increases in vascular pressure. This is the first study to demonstrate a role for the glycocalyx in whole lung mechanotransduction and has important implications in understanding the regulation of vascular permeability in the context of vascular pressure, fluid status, and ventilation strategies.