Question: 

Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for impaired tissue perfusion in diabetes. Since activation of the PPARg transcription factor has been shown to decrease radical stress and to enhance angiogenesis, we hypothesized that pioglitazone might preserve the microcirculation independently of its antihyperglycemic action.

Methods: 

Male Wistar rats were rendered diabetic by streptozotocin, and after 1 week were treated with pioglitazone in chow for 12 weeks. Capillary density was determined in heart and skeletal muscle by means of PECAM-1 immunostaining. Caspase activity and mRNA expression of HIF-related factors were analysed as parameters to detect apoptosis and angiogenesis.

Results: 

Capillary density decreased progressively in quadriceps muscle of the diabetic, hyperglycemic animals (from 971/mm² to 475/mm² during 13 weeks). Pioglitazone did not influence plasma glucose levels, left ventricular or body weight, but substantially preserved capillary densities compared to untreated controls (748/mm² vs. 385/mm² in m. quadriceps and 1650/mm² vs. 1076/mm² in left vetricular myocardium) after 13 weeks of diabetes. No anti-apoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of HIF-3a and PGC-1a mRNA as well as VEGF protein was observed, possibly as a consequence of improved vascularization.

Conclusion: 

Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control. This appears to be due to vessel stabilization rather than due to VEGF induced angiogenesis.