Abstract-The endothelial glycocalyx is a hydrated mesh of polysaccharides and adsorbed plasma proteins that forms the true interface between the flowing blood and the endothelium. We hypothesized in the present study that competitive binding of heparin to glycocalyx-associated proteins would affect glycocalyx barrier properties and mechanotransduction of shear stress to the endothelium. In anesthetized mice, the clearance of 70-kDa dextrans from the circulation was increased (PϽ0.05 versus saline) 1 hour after heparin (1.25 U) and glycocalyx degradation with hyaluronidase (35 U; amount cleared in 30 minutes after saline: 11Ϯ5%; after heparin: 45Ϯ8%; after hyaluronidase: 30Ϯ3%). Clearance of 40-kDa dextrans increased (PϽ0.05 versus saline) to a lesser extent after both treatments (saline: 46Ϯ3%; heparin: 60Ϯ5%; hyaluronidase: 60Ϯ2%). The dilator response of second-order arterioles in cremaster muscle during reactive hyperemia was reduced for Յ90 minutes after heparin as reflected by a decrease (Pϭ0.008) in t 50 of diameter recovery, and this effect was associated with a diminished NO bioavailability. Infusion of hyaluronidase resulted in reductions (PϽ0.05) in baseline and peak reactive hyperemic diameter, whereas, despite an increase in wall shear rate at the beginning of reactive hyperemia, t 50 of diameter recovery was not affected. In conclusion, our data in mice show that a heparin challenge is associated with increased vascular leakage of dextrans and impaired arteriolar vasodilation during reactive hyperemia. Our data suggest that protein-heparan sulfate interactions are important for a functional glycocalyx.

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Experimental evidence suggests gender differences in atherogenic susceptibility. Given the role of the endothelial glycocalyx in vascular homeostasis, we compared in the present study systemic glycocalyx volumes in anesthetized female (F; n=6) and male (M; n=7) C57Bl/6 mice (~25 g body weigth (BW)). Systemic glycocalyx volume (Vg, in ml/kg BW) was determined from the difference in distribution volume (Vd, in ml/kg BW) of FITC‐labelled 70 kDa dextrans (D70), used as plasma tracer, and Texas Red‐labelled 40 kDa dextrans (D40), which have full access to the glycocalyx domain. Tracers were simultaneously infused into the jugular vein and Vd calculated from the initial plasma concentration. Vd for D70 was not different between F (33 ± 4) and M (38 ± 1), but Vd for D40 was smaller (P=0.05) in F (37 ± 4) compared to M (46 ± 2), resulting in a smaller (P<0.005) Vg in F (3.7 ± 0.9) than in M (8.0 ± 0.7). True circulating plasma volume (Vp, in ml/kg BW) was subsequently derived from the dilution of NaF labelled red blood cells and hematocrit, and was not different between F (26 ± 2, n=4) and M (26 ± 2, n=5). In conclusion, our data show the presence of a gender difference in systemic glycocalyx volume in mice. The 50% reduction in glycocalyx volume in female mice might underlie their increased susceptibility to the development of atherosclerosis. Supported by Established Investigatorship from Netherlands Heart Foundation (#2005T037, to HV).