title: Pioglitazone prevents capillary rarefaction in streptozotocin-diabetic rats independently of glucose control and vascular endothelial growth factor expression.
abstract: OBJECTIVE
  Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-γ transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear.
  
  
  METHODS
  Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined.
  
  
  RESULTS
  Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm2 to 475/mm2 in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3α and PPAR coactivator-1α (PGC-1α) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization.
  
  
  CONCLUSIONS
  Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Ashoff
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Reinhard
authors.initials: R
authors.lastname: Eggers
authors.forename: Olaf
authors.initials: O
authors.lastname: Jöhren
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis*; D002196:Capillaries / Q000187:drug effects* / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D047495:PPAR gamma / Q000502:physiology; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; D013311:Streptozocin; D000077205:Pioglitazone