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

Abstract

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.

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…Another component of the alveolar-capillary barrier that has been recognized to be a critical regulator of barrier integrity is the endothelial glycocalyx, a dynamic luminal layer of glycoproteins, glycolipids, proteoglycans, and glycosaminoglycans (43, 116). Recently, it became evident that the glycocalyx actively regulates barrier function via mechanotransduction (59) and that depletion of sialic acid, which is typically found at the distal ends of carbohydrate chains and contributes significantly to the overall negative charge of cell surfaces, leads to endothelial barrier dysfunction (39), demonstrating the importance of glycocalyx composition in barrier integrity.…”

Preliminary in vitro analysis of mechanism of cardiac microvascular endothelial barrier function

“…Along with the extension of life expectancy, heart failure has attracted attention in China (Dull et al, 2012). Pathogenesis of heart failure had not been clarified hitherto.…”

Heparan Sulfate in the Developing, Healthy, and Injured Lung

“…This gel-like, fully hydrated ESL contributes to the endothelial barrier to fluid and protein, transduces vascular shear stress into endothelial nitric oxide (NO) synthesis, and regulates the availability of cell membrane adhesion molecules to circulating leukocytes (15). Accordingly, enzymatic HS degradation causes collapse of pulmonary ESL thickness (16), leading to lung edema (17,18), aberrant pressure-induced endothelial NO synthesis (17,18), and lung inflammation (16).…”