title: Halofuginone stimulates adaptive remodeling and preserves re-endothelialization in balloon-injured rat carotid arteries.
abstract: BACKGROUND
  Three major processes, constrictive vessel remodeling, intimal hyperplasia (IH), and retarded re-endothelialization, contribute to restenosis after vascular reconstructions. Clinically used drugs inhibit IH but delay re-endothelialization and also cause constrictive remodeling. Here we have examined halofuginone, an herbal derivative, for its beneficial effects on vessel remodeling and differential inhibition of IH versus re-endothelialization.
  
  
  RESULTS
  Two weeks after perivascular application to balloon-injured rat common carotid arteries, halofuginone versus vehicle (n=6 animals) enlarged luminal area 2.14-fold by increasing vessel size (adaptive remodeling; 123%), reducing IH (74.3%) without inhibiting re-endothelialization. Consistent with its positive effect on vessel expansion, halofuginone reduced collagen type 1 (but not type 3) production in injured arteries as well as that from adventitial fibroblasts in vitro. In support of its differential effects on IH versus re-endothelialization, halofuginone produced greater inhibition of vascular smooth muscle cell versus endothelial cell proliferation at concentrations ≈50 nmol/L. Furthermore, halofuginone at 50 nmol/L effectively blocked Smad3 phosphorylation in smooth muscle cells, which is known to promote smooth muscle cell proliferation, migration, and IH, but halofuginone had no effect on phospho-Smad3 in endothelial cells.
  
  
  CONCLUSIONS
  Periadventitial delivery of halofuginone dramatically increased lumen patency via adaptive remodeling and selective inhibition of IH without affecting endothelium recovery. Halofuginone is the first reported small molecule that has favorable effects on all 3 major processes involved in restenosis.
authors: From the Department of Surgery, University of Wisconsin, Madison. guo@surgery.wisc.edu.
authors: Lian-Wang
authors: LW
authors: Guo
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Bowen
authors: B
authors: Wang
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Shakti A
authors: SA
authors: Goel
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Christopher
authors: C
authors: Little
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Toshio
authors: T
authors: Takayama
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Xu Dong
authors: XD
authors: Shi
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Drew
authors: D
authors: Roenneburg
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: Daniel
authors: D
authors: DiRenzo
authors: From the Department of Surgery, University of Wisconsin, Madison.
authors: K Craig
authors: KC
authors: Kent
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D000800:Angioplasty, Balloon; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000601:surgery; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D023421:Models, Animal; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000473:pathology; D009928:Organ Specificity; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D011183:Postoperative Complications / Q000517:prevention & control*; D052999:Quinazolinones / Q000008:administration & dosage* / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000378:metabolism; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D024042:Collagen Type I; D010880:Piperidines; D052999:Quinazolinones; D051900:Smad3 Protein; C010176:halofuginone
keywords: Smad3 protein; cell proliferation; collagen; halofuginone; vascular endothelium; vascular patency