title: Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury.
abstract: OBJECTIVE
  Polyamines are organic polycations playing an essential role in cell proliferation and differentiation, as well as in cell contractility, migration and apoptosis. These processes are known to contribute to restenosis, a pathophysiological process often occurring in patients submitted to revascularization procedures. We aimed to test the effect of α-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, on vascular cell pathophysiology in vitro and in a rat model of carotid arteriotomy-induced (re)stenosis.
  
  
  METHODS
  The effect of DFMO on primary rat smooth muscle cells (SMCs) and mouse microvascular bEnd.3 endothelial cells (ECs) was evaluated through the analysis of DNA synthesis, polyamine concentration, cell viability, cell cycle phase distribution and by RT-PCR targeting cyclins and genes belonging to the polyamine pathway. The effect of DFMO was then evaluated in arteriotomy-injured rat carotids through the analysis of cell proliferation and apoptosis, RT-PCR and immunohistochemical analysis of differential gene expression.
  
  
  RESULTS
  DFMO showed a differential effect on SMCs and on ECs, with a marked, sustained anti-proliferative effect of DFMO at 3 and 8 days of treatment on SMCs and a less pronounced, late effect on bEnd.3 ECs at 8 days of DFMO treatment. DFMO applied perivascularly in pluronic gel at arteriotomy site reduced subsequent cell proliferation and preserved smooth muscle differentiation without affecting the endothelial coverage. Lumen area in DFMO-treated carotids was 49% greater than in control arteries 4 weeks after injury.
  
  
  CONCLUSIONS
  Our data support the key role of polyamines in restenosis and suggest a novel therapeutic approach for this pathophysiological process.
authors.affiliation: Dept. of Experimental Medicine, Second University of Naples, Italy; Excellence Research Centre for Cardiovascular Diseases, Second University of Naples, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Forte
authors.forename: Mario
authors.initials: M
authors.lastname: Grossi
authors.forename: Karolina M
authors.initials: KM
authors.lastname: Turczynska
authors.forename: Kaj
authors.initials: K
authors.lastname: Svedberg
authors.forename: Barbara
authors.initials: B
authors.lastname: Rinaldi
authors.forename: Maria
authors.initials: M
authors.lastname: Donniacuo
authors.forename: Anders
authors.initials: A
authors.lastname: Holm
authors.forename: Bo
authors.initials: B
authors.lastname: Baldetorp
authors.forename: Mariano
authors.initials: M
authors.lastname: Vicchio
authors.forename: Marisa
authors.initials: M
authors.lastname: De Feo
authors.forename: Pasquale
authors.initials: P
authors.lastname: Santè
authors.forename: Umberto
authors.initials: U
authors.lastname: Galderisi
authors.forename: Liberato
authors.initials: L
authors.lastname: Berrino
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
authors.forename: Per
authors.initials: P
authors.lastname: Hellstrand
authors.forename: Bengt-Olof
authors.initials: BO
authors.lastname: Nilsson
authors.forename: Marilena
authors.initials: M
authors.lastname: Cipollaro
mesh_terms: D000818:Animals; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000201:enzymology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000518:Eflornithine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D065108:Ornithine Decarboxylase Inhibitors; D009955:Ornithine Decarboxylase; D000518:Eflornithine
keywords: Endothelial cells; Negative remodeling; Ornithine decarboxylase; Restenosis; Smooth muscle cells; α-Difluoromethylornithine