Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARgamma stimulation.
BACKGROUND
Type 2 diabetes mellitus (T2DM) is commonly associated with both microvascular and macrovascular complications and a strong correlation exists between glycaemic control and the incidence and progression of vascular complications. Pioglitazone, a Peroxisome proliferator-activated receptor-gamma (PPARgamma) ligand indicated for therapy of type T2DM, induces vascular effects that seem to occur independently of glucose lowering.


METHODS
By using a hindlimb ischemia murine model, in this study we have found that pioglitazone restores the blood flow recovery and capillary density in ischemic muscle of diabetic mice and that this process is associated with increased expression of Vascular Endothelial Growth Factor (VEGF). Importantly, these beneficial effects are abrogated when endogenous Akt is inhibited; furthermore, the direct activation of PPARgamma, with its selective agonist GW1929, does not restore blood flow recovery and capillary density. Finally, an important collateral vessel growth is obtained with combined treatment with pioglitazone and selective PPARgamma inhibitor GW9662.


CONCLUSIONS
These data demonstrate that Akt-VEGF pathway is essential for ischemia-induced angiogenic effect of pioglitazone and that pioglitazone exerts this effect via a PPARgamma independent manner.
Biscetti
Federico
F
Laboratory of Vascular Biology and Genetics, Department of Medicine, A Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy. f.biscetti@gmail.com
Straface
Giuseppe
G
Arena
Vincenzo
V
Stigliano
Egidio
E
Pecorini
Giovanni
G
Rizzo
Paola
P
De Angelis
Giulia
G
Iuliano
Luigi
L
Ghirlanda
Giovanni
G
Flex
Andrea
A
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D003097:Collateral Circulation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007511:Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051058:Oncogene Protein v-akt / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D000077205:Pioglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D001577:Benzophenones; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D014443:Tyrosine; D051058:Oncogene Protein v-akt; D000077205:Pioglitazone; C120099:GW 1929