Inhibiting the production of hyaluronan disrupts the endothelial glycocalyx and impairs arteriogenesis

The process of arteriogenesis, the widening and vascular remodeling of existing collateral arteries, is dependent on the ability of the endothelial cells to sense an increase in shear stress upon increased flow due to a proximal blocked feeding artery. We hypothesize that mechanotransduction of shear stress by the endothelial glycocalyx plays a crucial role in this process. In the current study glycocalyx was treated with the hyaluronan synthesis inhibitor 4‐methylesculetin (4ME), and its effect on arteriogenesis was tested in C57BL6/J mice. Mice (C57BL6/J, ♂ on normal chow) received 14 μg/hr of 4ME intravenously via an osmotic mini‐pump one week before intervention and throughout the two week recovery period. Control mice received a DMSO/saline infusion. Using the mouse hindlimb ligation model, the femoral artery was ligated and perfusion recovery was monitored at week two by Laser Doppler. Hindlimb perfusion was significantly impaired on day 14 after ligation with the 4ME infused mice, compared to control (54 +/− 19% (n=6) vs. 107 +/− 3% (n=3)). These results suggest that the endothelial glycocalyx might play a role in the initial shear stress sensing and vascular remodeling and thus maturation of the collateral vasculature. This work is supported by a grant from The Dutch Heart Foundation.