title: Enhanced neointimal fibroblast, myofibroblast content and altered extracellular matrix composition: Implications in the progression of human peripheral artery restenosis.
abstract: Neointimal cellular proliferation of fibroblasts and myofibroblasts is documented in coronary artery restenosis, however, their role in peripheral arterial disease (PAD) restenosis remains unclear. Our aim was to investigate the role of fibroblasts, myofibroblasts, and collagens in restenotic PAD.
  
  
  
  Nineteen PAD restenotic plaques were compared with 13 de novo plaques. Stellate cells (H&E), fibroblasts (FSP-1), myofibroblasts (α-actin/vimentin/FSP-1), cellular proliferation (Ki-67), and apoptosis (caspase-3 with poly ADP-ribose polymerase) were evaluated by immunofluorescence. Collagens were evaluated by picro-sirius red stain with polarization microscopy. Smooth muscle myosin heavy chain (SMMHC), IL-6 and TGF-β cytokines were analyzed by immunohistochemistry.
  
  
  
  Restenotic plaques demonstrated increased stellate cells (2.7 ± 0.15 vs.1.3 ± 0.15) fibroblasts (2282.2 ± 85.9 vs. 906.4 ± 134.5) and myofibroblasts (18.5 ± 1.2 vs.10.6 ± 1.0) p = 0.0001 for all comparisons. In addition, fibroblast proliferation (18.4% ± 1.2 vs.10.4% ± 1.1; p = 0.04) and apoptosis (14.6% ± 1.3 vs.11.2% ± 0.6; p = 0.03) were increased in restenotic plaques. Finally, SMMHC (2.6 ± 0.12 vs.1.4 ± 0.15; p = 0.0001), type III collagen density (0.33 ± 0.06 vs. 0.17 ± 0.07; p = 0.0001), IL-6 (2.08 ± 1.7 vs.1.03 ± 2.0; p = 0.01), and TGF-β (1.80 ± 0.27 vs. 1.11 ± 0.18; p = 0.05) were increased in restenotic plaques.
  
  
  
  Our study suggests proliferation and apoptosis of fibroblast and myofibroblast with associated increase in type III collagen may play a role in restenotic plaque progression. Understanding pathways involved in proliferation and apoptosis in neointimal cells, may contribute to future therapeutic interventions for the prevention of restenosis in PAD.
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Krishnan
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: purushothaman.kothandaraman@mountsinai.org.
authors.forename: K-Raman
authors.initials: KR
authors.lastname: Purushothaman
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Meerarani
authors.initials: M
authors.lastname: Purushothaman
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Irene C
authors.initials: IC
authors.lastname: Turnbull
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Tarricone
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Vasquez
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Jain
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Usman
authors.initials: U
authors.lastname: Baber
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Rheoneil A
authors.initials: RA
authors.lastname: Lascano
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Annapoorna S
authors.initials: AS
authors.lastname: Kini
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Samin K
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: The Zena and Michael A. Weiner Cardiovascular Institute, The Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Department of Medicine/Cardiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Moreno
mesh_terms: D000199:Actins / Q000378:metabolism; D000368:Aged; D017209:Apoptosis; D001158:Arteries / Q000473:pathology*; D017073:Atherectomy; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D024061:Collagen Type III / Q000378:metabolism; D003251:Constriction, Pathologic / Q000473:pathology; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D058426:Neointima / Q000378:metabolism*; D058729:Peripheral Arterial Disease / Q000378:metabolism*; D015995:Prevalence; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014661:Vasoconstriction
chemical_list: D000199:Actins; D024061:Collagen Type III; C508600:IL6 protein, human; D015850:Interleukin-6; D016212:Transforming Growth Factor beta; C505407:CASP3 protein, human; D053148:Caspase 3; D018995:Myosin Heavy Chains
keywords: Atherosclerosis; Collagens; Neointimal proliferation; Peripheral arterial disease; Restenosis