Enhancement of Shear Dependent Accumulation of Glycans on Endothelium by Inhibition of Matrixmetalloproteases (MMPs)

Prior studies have demonstrated that following 60 min of ischemia, the glycan content of the endothelial cell (EC) glycocalyx increased significantly by 30%, as evidenced by accumulation of lectin coated fluorescent microspheres (FLMs, 0.1 μm dia). The present studies aimed to examine the role of MMP activity in affecting this relationship in post‐capillary venules of mesentery (rat) in light of reductions of shear rates on the EC. Wall shear rates in venules were rapidly reduced by systemic blood withdrawal to produce hemorrhagic hypotension. Reductions in wall shear rates from 600 sec −1 in the resting state, to 100 sec −1 in the low flow state were induced and corresponded to a 50% reduction in red cell velocity. The accumulation of lectin (BS‐1) coated FLMs was monitored during the initial reduction over a 10 min period and the subsequent 20 min of low flow. During this 30 min period, FLM adhesion increased 50% from 10 to 15 FLMs adhered per 100 μm of venule length. Inhibition of MMP activity with 0.5 μM doxycycline caused a two‐fold increase in FLM adhesion at all shear rates, and doubled the slope of the FLM accumulation vs. shear rate. Thus, inhibition of normal MMP activity by doxycycline caused a two‐fold increase in lectin binding sites on the EC surface, which may facilitate leukocyte adhesion in the low flow state. Supported by NIH R01 HL‐39286.