TY - JOUR
T1 - The endothelial glycocalyx as a barrier to leukocyte adhesion and its mediation by extracellular proteases
AU - Lipowsky, Herbert H.
N1 - Funding Information:
This research was supported in part by NIH R01-HL39286-20.
PY - 2012/4
Y1 - 2012/4
N2 - The endothelial cell (EC) surface is coated with a layer of polysaccharides linked to membrane-bound and trans-membrane proteoglycans that comprise the glycocalyx, which is augmented by adsorbed proteins derived from the blood stream. This surface layer has been shown to affect hemodynamics in small blood vessels of the microcirculation, the resistance to flow, and leukocyte (WBC) to EC adhesion. Parallel studies of WBC-EC adhesion in response to chemo-attractants and cytokines, and shedding of constituents of the glycocalyx, have suggested a role for activation of extracellular proteases in mediating the dynamics of WBC adhesion in response to inflammatory and ischemic stimuli. Likely candidates among the many proteases present are the matrix metalloproteases (MMPs). Inhibition of MMP activation with sub-antimicrobial doses of doxycycline, or zinc chela-tors, has also inhibited WBC adhesion and shedding of glycans from the EC surface in response to the chemoattrac-tant fMLP. Taken together, these studies suggest that shedding of the EC glycocalyx exposes adhesion receptors and thus enhances WBC-EC adhesion. Future therapeutic strategies for treating pathologies such as the low flow state and inflammation may benefit by further exploration of the mechanics of the glycocalyx in light of protease activation and shear-dependent effects.
AB - The endothelial cell (EC) surface is coated with a layer of polysaccharides linked to membrane-bound and trans-membrane proteoglycans that comprise the glycocalyx, which is augmented by adsorbed proteins derived from the blood stream. This surface layer has been shown to affect hemodynamics in small blood vessels of the microcirculation, the resistance to flow, and leukocyte (WBC) to EC adhesion. Parallel studies of WBC-EC adhesion in response to chemo-attractants and cytokines, and shedding of constituents of the glycocalyx, have suggested a role for activation of extracellular proteases in mediating the dynamics of WBC adhesion in response to inflammatory and ischemic stimuli. Likely candidates among the many proteases present are the matrix metalloproteases (MMPs). Inhibition of MMP activation with sub-antimicrobial doses of doxycycline, or zinc chela-tors, has also inhibited WBC adhesion and shedding of glycans from the EC surface in response to the chemoattrac-tant fMLP. Taken together, these studies suggest that shedding of the EC glycocalyx exposes adhesion receptors and thus enhances WBC-EC adhesion. Future therapeutic strategies for treating pathologies such as the low flow state and inflammation may benefit by further exploration of the mechanics of the glycocalyx in light of protease activation and shear-dependent effects.
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U2 - 10.1007/s10439-011-0427-x
DO - 10.1007/s10439-011-0427-x
M3 - Article
C2 - 21984514
AN - SCOPUS:84862139767
SN - 0090-6964
VL - 40
SP - 840
EP - 848
JO - Annals of Biomedical Engineering
JF - Annals of Biomedical Engineering
IS - 4
ER -