title: Endothelial cell repopulation after stenting determines in-stent neointima formation: effects of bare-metal vs. drug-eluting stents and genetic endothelial cell modification.
abstract: OBJECTIVE
  Understanding endothelial cell repopulation post-stenting and how this modulates in-stent restenosis is critical to improving arterial healing post-stenting. We used a novel murine stent model to investigate endothelial cell repopulation post-stenting, comparing the response of drug-eluting stents with a primary genetic modification to improve endothelial cell function.
  
  
  RESULTS
  Endothelial cell repopulation was assessed en face in stented arteries in ApoE(-/-) mice with endothelial-specific LacZ expression. Stent deployment resulted in near-complete denudation of endothelium, but was followed by endothelial cell repopulation, by cells originating from both bone marrow-derived endothelial progenitor cells and from the adjacent vasculature. Paclitaxel-eluting stents reduced neointima formation (0.423 ± 0.065 vs. 0.240 ± 0.040 mm(2), P = 0.038), but decreased endothelial cell repopulation (238 ± 17 vs. 154 ± 22 nuclei/mm(2), P = 0.018), despite complete strut coverage. To test the effects of selectively improving endothelial cell function, we used transgenic mice with endothelial-specific overexpression of GTP-cyclohydrolase 1 (GCH-Tg) as a model of enhanced endothelial cell function and increased NO production. GCH-Tg ApoE(-/-) mice had less neointima formation compared with ApoE(-/-) littermates (0.52 ± 0.08 vs. 0.26 ± 0.09 mm(2), P = 0.039). In contrast to paclitaxel-eluting stents, reduced neointima formation in GCH-Tg mice was accompanied by increased endothelial cell coverage (156 ± 17 vs. 209 ± 23 nuclei/mm(2), P = 0.043).
  
  
  CONCLUSIONS
  Drug-eluting stents reduce not only neointima formation but also endothelial cell repopulation, independent of strut coverage. In contrast, selective targeting of endothelial cell function is sufficient to improve endothelial cell repopulation and reduce neointima formation. Targeting endothelial cell function is a rational therapeutic strategy to improve vascular healing and decrease neointima formation after stenting.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Douglas
authors.forename: Erik
authors.initials: E
authors.lastname: Van Kampen
authors.forename: Ashley B
authors.initials: AB
authors.lastname: Hale
authors.forename: Eileen
authors.initials: E
authors.lastname: McNeill
authors.forename: Jyoti
authors.initials: J
authors.lastname: Patel
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Crabtree
authors.forename: Ziad
authors.initials: Z
authors.lastname: Ali
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hoerr
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Alp
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D050197:Atherosclerosis / Q000473:pathology*; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058426:Neointima / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D015607:Stents; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D005343:Fibrinolytic Agents; D050257:Tubulin Modulators; D017239:Paclitaxel; D001241:Aspirin