title: PPARγ activation inhibits cerebral arteriogenesis in the hypoperfused rat brain.
abstract: OBJECTIVE
  PPARγ stimulation improves cardiovascular (CV) risk factors, but without improving overall clinical outcomes. PPARγ agonists interfere with endothelial cell (EC), monocyte and smooth muscle cell (SMC) activation, function and proliferation, physiological processes critical for arterial collateral growth (arteriogenesis). We therefore assessed the effect of PPARγ stimulation on cerebral adaptive and therapeutic collateral growth.
  
  
  METHODS
  In a rat model of adaptive cerebral arteriogenesis (3-VO), collateral growth and function were assessed (i) in controls, (ii) after PPARγ stimulation (pioglitazone 2.8 mg kg(-1); 10 mg kg(-1) compared with metformin 62.2 mg kg(-1) or sitagliptin 6.34 mg kg(-1)) for 21 days or (iii) after adding pioglitazone to G-CSF (40 μg kg(-1) every other day) to induce therapeutic arteriogenesis for 1 week. Pioglitazone effects on endothelial and SMC morphology and proliferation, monocyte activation and migration were studied.
  
  
  RESULTS
  PPARγ stimulation decreased cerebrovascular collateral growth and recovery of hemodynamic reserve capacity (CVRC controls: 12 ± 7%; pio low: -2 ± 9%; pio high: 1 ± 7%; metformin: 9 ± 13%; sitagliptin: 11 ± 12%), counteracted G-CSF-induced therapeutic arteriogenesis and interfered with EC activation, SMC proliferation, monocyte activation and migration.
  
  
  CONCLUSIONS
  Pharmacologic PPARγ stimulation inhibits pro-arteriogenic EC activation, monocyte function, SMC proliferation and thus adaptive as well as G-CSF-induced cerebral arteriogenesis. Further studies should evaluate whether this effect may underlie the CV risk associated with thiazolidinedione use in patients.
authors.affiliation: Center for Cardiovascular Research (CCR), Richard-Thoma-Laboratories for Arteriogenesis, Charité - Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Duelsner
authors.forename: N
authors.initials: N
authors.lastname: Gatzke
authors.forename: P
authors.initials: P
authors.lastname: Hillmeister
authors.forename: J
authors.initials: J
authors.lastname: Glaser
authors.forename: A
authors.initials: A
authors.lastname: Zietzer
authors.forename: S
authors.initials: S
authors.lastname: Nagorka
authors.forename: D
authors.initials: D
authors.lastname: Janke
authors.forename: J
authors.initials: J
authors.lastname: Pfitzner
authors.forename: P
authors.initials: P
authors.lastname: Stawowy
authors.forename: H
authors.initials: H
authors.lastname: Meyborg
authors.forename: D
authors.initials: D
authors.lastname: Urban
authors.forename: A
authors.initials: A
authors.lastname: Bondke Persson
authors.forename: I R
authors.initials: IR
authors.lastname: Buschmann
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D047495:PPAR gamma / Q000378:metabolism*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D043925:Angiogenesis Inducing Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: PPARγ; arteriogenesis; blood flow; collateral growth; glitazone