Endothelial Cell Glycocalyx Modulates Immobilization of Leukocytes at the Endothelial Surface

Abstract

Objective-A thick endothelial glycocalyx provides the endothelial surface with a nonadherent shield. Oxidized LDL (Ox-LDL) degrades the endothelial glycocalyx. We hypothesized that glycocalyx degradation stimulates leukocyteendothelial cell adhesion, whereas intravascular supplementation with sulfated polysaccharides reconstitutes the endothelial glycocalyx and attenuates Ox-LDL-induced leukocyte-endothelial cell adhesion. Methods and Results-Degradation of the endothelial glycocalyx by local microinjection of heparitinase (10 to 50 U/mL) into mouse cremaster venules dose-dependently increased the number of adherent leukocytes. Systemic administration of Ox-LDL (0.4 mg/100 g body weight) induced 10.1Ϯ0.9 adherent leukocytes/100 m at 60 minutes. In the venules perfused with 500-kDa dextran sulfate (1 mg/mL), the number of adherent leukocytes at 60 minutes after Ox-LDL bolus application was not influenced (9.2Ϯ1.0 leukocytes/100 m). However, the venules locally perfused with heparan sulfate (10 mg/mL) or heparin (1 mg/mL) displayed a significantly lower number of adherent leukocytes induced by Ox-LDL: 5.1Ϯ0.7 and 5.4Ϯ0.9 leukocytes/100 m, respectively (PϽ0.05). Fluorescently labeled heparan sulfate and heparin, but not dextran sulfate, attached to the venule luminal surface after Ox-LDL administration. Key Words: glycocalyx Ⅲ leukocytes Ⅲ oxidized LDL Ⅲ heparin T he endothelial glycocalyx provides the endothelial surface with a negatively charged coating that contributes to the antiadhesive nature of the endothelial cell surface. 1,2 In the presence of inflammatory stimuli, the endothelial surface loses its nonadhesiveness because of the activation of adhesion molecules and becomes accessible to leukocytes. There is evidence that activation of adhesion molecules is associated with changes in the cell-surface glycocalyx. 2-4 Indeed, the glycocalyx occupies a large domain at the endothelial surface, 5,6 which most probably influences the adhesion process. In this investigation, we studied the effect of endothelial glycocalyx condition on leukocyte-endothelial cell adhesion. Conclusions-EndothelialUnderstanding the role of the endothelial glycocalyx in leukocyte-endothelial cell adhesion has direct relevance for atherosclerosis-related conditions, such as hypercholesterolemia and the plasma presence of oxidized lipoproteins, which are associated with increased leukocyte recruitment 7,8 and degradation of the endothelial glycocalyx. 9 -11 Noteworthy, early modifications of endothelial cells during diet-induced hypercholesterolemia are represented by a decreased thickness and anionic charge of the endothelial glycocalyx and by changes in its biochemical composition. 9,10 Degradation of the endothelial glycocalyx is also induced by oxidized LDL (Ox-LDL in clinically relevant doses and is associated with a parallel increase in endothelial surface adhesiveness. 11 The first aim of the present study was to induce a primary alteration of the thickness and charge of the endothelial glycocalyx by enzyme treatment and to inves...

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