HEPARIN HEPARAN SULFATE CHELATION INHIBITS CONTROL OF VASCULAR REPAIRBY TISSUE-ENGINEERED ENDOTHELIAL-CELLS/

The relative importance of heparin-like compounds in mediating vascula r repair is unclear. We investigated how protamine, a chelator of hepa rin, affected endothelial cell inhibition of vascular smooth muscle ce ll growth and intimal hyperplasia. The 52% (P < 0.001) reduction in sm ooth muscle cell proliferation produced by postconfluent endothelial c ell-conditioned medium was entirely reversed by pretreatment of medium with heparinase and heparitinase and was inhibited in a dose-dependen t fashion by the coadministration of protamine. Pretreatment of condit ioned medium with heparinase and heparitinase largely prevented protam ine's mitogenic activity, suggesting that protamine affects growth by interacting with heparin-like compounds. Perivascular implantation of polymer-engrafted endothelial cells reduced neointima formation in den uded rat carotid arteries by 92% (P < 0.001) and cell proliferation by 81% (P < 0.001). Coadministration of protamine abolished the inhibito ry potential of the cell implants, resulting in a nearly twofold exace rbation of intimal hyperplasia compared with controls (P < 0.001). Thu s heparin-like molecules are essential to the biochemical regulation o f vascular repair provided by endothelial cells, and the continued rou tine clinical use of heparin chelators, like protamine, may be questio nable.