Loss of Endothelial Glycocalyx During Acute Hyperglycemia Coincides With Endothelial Dysfunction and Coagulation Activation In Vivo

Abstract

Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability. The systemic glycocalyx volume was estimated by comparing the distribution volume of a glycocalyx permeable tracer (dextran 40) with that of a glycocalyx impermeable tracer (labeled erythrocytes) in 10 healthy male subjects. Measurements were performed in random order on five occasions: two control measurements, two measurements during normoinsulinemic hyperglycemia with or without N-acetylcysteine (NAC) infusion, and one during mannitol infusion. Glycocalyx measurements were reproducible (1.7 ؎ 0.2 vs. 1.7 ؎ 0.3 l). Hyperglycemia reduced glycocalyx volume (to 0.8 ؎ 0.2 l; P < 0.05), and NAC was able to prevent the reduction (1.4 ؎ 0.2 l). Mannitol infusion had no effect on glycocalyx volume (1.6 ؎ 0.1 l). Hyperglycemia resulted in endothelial dysfunction, increased plasma hyaluronan levels (from 70 ؎ 6 to 112 ؎ 16 ng/ml; P < 0.05) and coagulation activation (prothrombin activation fragment 1 ؉ 2: from 0.4 ؎ 0.1 to 1.1 ؎ 0.2 nmol/l; D-dimer: from 0.27 ؎ 0.1 to 0.55 ؎ 0.2 g/l; P < 0.05). Taken together, these data indicate a potential role for glycocalyx perturbation in mediating vascular dysfunction during hyperglycemia. Diabetes 55:480 -486, 2006 P atients with diabetes have increased vascular vulnerability to atherogenic insults, leading to accelerated atherogenesis. Although atherogenesis is in part due to the increased prevalence of traditional cardiovascular risk factors, these factors cannot fully explain the propensity toward vascular complications in diabetic patients (1). Hyperglycemia itself has been shown to induce a wide array of downstream effects that adversely affect the protective capacity of the vessel wall (2). Hyperglycemia has been associated with enhanced endothelial permeability, increased leukocyte-endothelium adhesion, and impaired nitric oxide (NO) bioavailability (3-5). Despite clear progress in understanding the underlying pathophysiological mechanisms contributing to this vascular dysfunction, it has proven difficult to unravel a final common pathway for the increased vascular vulnerability under hyperglycemic conditions (6).The glycocalyx covers the endothelium and consists of endothelial cell-derived proteoglycans, glycoproteins, and adsorbed plasma proteins. This layer has been shown to orchestrate vascular homeostasis (7). Its thickness (up to 1 m) may explain its potent antiadhesive effects on leukocytes and platelets (8,9). Hyaluronan glycosaminoglycans, one of the major constituents of the glycocalyx, are crucial for maintaining endothelial barrier properties for plasma macromolecules (10). The glycocalyx also serves as a mechanosensor of shear stress, mediating shear-induced release of NO by endothelial cells (11-13). In fact, selective perturbation of the g...

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