Heparin/heparan sulfate chelation inhibits control of vascular repair by tissue-engineered endothelial cells.
The relative importance of heparin-like compounds in mediating vascular repair is unclear. We investigated how protamine, a chelator of heparin, affected endothelial cell inhibition of vascular smooth muscle cell growth and intimal hyperplasia. The 52% (P < 0.001) reduction in smooth muscle cell proliferation produced by postconfluent endothelial cell-conditioned medium was entirely reversed by pretreatment of medium with heparinase and heparitinase and was inhibited in a dose-dependent fashion by the coadministration of protamine. Pretreatment of conditioned medium with heparinase and heparitinase largely prevented protamine's mitogenic activity, suggesting that protamine affects growth by interacting with heparin-like compounds. Perivascular implantation of polymerengrafted endothelial cells reduced neointima formation in denuded rat carotid arteries by 92% (P < 0.001) and cell proliferation by 81% (P < 0.001). Coadministration of protamine abolished the inhibitory potential of the cell implants, resulting in a nearly twofold exacerbation of intimal hyperplasia compared with controls (P < 0.001). Thus heparin-like molecules are essential to the biochemical regulation of vascular repair provided by endothelial cells, and the continued routine clinical use of heparin chelators, like protamine, may be questionable.
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Harvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Cambridge 02139, USA.
Ettenson
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Koo
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Edelman
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D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D017536:Carotid Artery, Common / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000502:physiology* / Q000637:transplantation*; D005781:Gelatin Sponge, Absorbable; D006493:Heparin / Q000502:physiology*; D006494:Heparin Antagonists / Q000494:pharmacology; D006497:Heparan Sulfate / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D011479:Protamines / Q000494:pharmacology*; D051381:Rats; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects / Q000502:physiology
D017077:Culture Media, Conditioned; D006493:Heparin; D006494:Heparin Antagonists; D006497:Heparan Sulfate; D011479:Protamines