Special article: the endothelial glycocalyx: emerging concepts in pulmonary edema and acute lung injury

Abstract

The endothelial glycocalyx is a dynamic layer of macromolecules at the luminal surface of vascular endothelium that is involved in fluid homeostasis and regulation. Its role in vascular permeability and edema formation is emerging but is still not well understood. In this special article, we highlight key concepts of endothelial dysfunction with regards to the glycocalyx and provide new insights into the glycocalyx as a mediator of processes central to the development of pulmonary edema and lung injury.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1

Transcapillary fluid flux: Classic Starling relationship versus active mechanotransduction. Classic Starling principle (black line) predicts a linear relationship between capillary pressure (cm H2O) and transcapillary fluid flux (μm/sec). The x-intercept is the point where plasma oncotic pressure equals capillary hydrostatic pressure, resulting in zero net fluid flux. During active endothelial mechanotransduction (maroon line), capillary hydrostatic pressure activates signaling pathways that increase endothelial permeability resulting in nonlinear dynamics and a higher water flux than would be predicted by the summation of net Starling forces. Classic Starling forces can predict fluid flux over short time intervals (seconds to minutes) while mechanotransduction pathways are time-dependent, requiring 10-20 minutes to manifest changes in endothelial permeability.

Figure 2

The glycocalyx is a complex layer of protetoglycans, glycosaminoglycans and glycolipids on the endothelial surface. (A) An intact glycocalyx limits water and protein flux into the cell-cell junction by forming a molecular filter over the junctional orifice. The glycocalyx also creates a scaffolding upon which serum proteins accumulate and form the immobile plasma layer directly adjacent to the vessel wall. Collectively, the glycocalyx and protein layer create the red blood cell exclusion zone used to determine the functional thickness of the glycocalyx. (B) During inflammation, proteases degrade the glycocalyx and endothelial cells shed constituents through cell-associated sheddases. Loss of the glycocalyx scaffolding eliminates the immobile plasma layer. Breakdown of the glycocalyx is associated with increased vascular permeability due to loss of the junctional barrier and opening of the intracellular junction, as evidence by increased water and protein flux through the junction. Note the protein-free space under the glycocalyx (left panel) that may significantly affect Starling forces across the cell-cell junction (see text for detail).

Figure 3

Schematic illustrating the hypothesized role of the glycocalyx in lung vascular mechanotransduction. Left: during static conditions, the glycocalyx maintains barrier function over the intercellular junction. Right: during increased vascular pressure, the increased hydraulic flow through the glycocalyx deforms or stresses the glycosaminoglycan (GAG) fibers, which in turn activates endothelial nitric oxide synthase (eNOS) and leads to barrier dysfunction. ΔPc, change in capillary pressure; Q, flow; ZO-1 and ZO-2, zonula occludens-1 and -2; vin, vinculin; VE-Cad, vascular endothelial cadherin; ECM, extracellular matrix (Adapted from Dull R, Cluff M, Kingston J, Hill D, Chen H, Hoehne S, Malleske D, Kaur R. Lung heparan sulfates modulate Kfc during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction. Am J Physiol Lung Cell Mol Physiol 2012;302:L816-28).