Blockade of advanced glycation end-product formation restores ischemia-induced angiogenesis in diabetic mice.
We hypothesized that formation of advanced glycation end products (AGEs) associated with diabetes reduces matrix degradation by metalloproteinases (MMPs) and contributes to the impairment of ischemia-induced angiogenesis. Mice were treated or not with streptozotocin (40 mg/kg) and streptozotocin plus aminoguanidine (AGEs formation blocker, 50 mg/kg). After 8 weeks of treatment, hindlimb ischemia was induced by right femoral artery ligature. Plasma AGE levels were strongly elevated in diabetic mice when compared with control mice (579 +/- 21 versus 47 +/- 4 pmol/ml, respectively; P < 0.01). Treatment with aminoguanidine reduced AGE plasma levels when compared with untreated diabetic mice (P < 0.001). After 28 days of ischemia, ischemic/nonischemic leg angiographic score, capillary density, and laser Doppler skin-perfusion ratios were 1.4-, 1.5-, and 1.4-fold decreased in diabetic mice in reference to controls (P < 0.01). Treatment with aminoguanidine completely normalized ischemia-induced angiogenesis in diabetic mice. We next analyzed the role of proteolysis in AGE formation-induced hampered neovascularization process. After 3 days of ischemia, MMP-2 activity and MMP-3 and MMP-13 protein levels were increased in untreated and aminoguanidine-treated diabetic mice when compared with controls (P < 0.05). Despite this activation of the MMP pathway, collagenolysis was decreased in untreated diabetic mice. Conversely, treatment of diabetic mice with aminoguanidine restored collagenolysis toward levels found in control mice. In conclusion, blockade of AGE formation by aminoguanidine normalizes impaired ischemia-induced angiogenesis in diabetic mice. This effect is probably mediated by restoration of matrix degradation processes that are disturbed as a result of AGE accumulation.
Tamarat
Radia
R
Institut National de la Santé et de la Recherche Médicale U541, Hôpital Lariboisière, Institut Federatif de Recherche Circulation-Paris 7, Université Paris 7-Denis Diderot, 75475 Paris Cedex 10, France.
Silvestre
Jean-Sébastien
JS
Huijberts
Maya
M
Benessiano
Joelle
J
Ebrahimian
Teni G
TG
Duriez
Micheline
M
Wautier
Marie-Paule
MP
Wautier
Jean Luc
JL
Lévy
Bernard I
BI
D000792:Angiography; D000818:Animals; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism; D003097:Collateral Circulation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004318:Doxycycline / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005263:Femoral Artery; D017127:Glycation End Products, Advanced / Q000097:blood*; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006614:Hindlimb / Q000098:blood supply / Q000000981:diagnostic imaging; D007511:Ischemia / Q000503:physiopathology*; D008026:Ligation; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000494:pharmacology; D012867:Skin / Q000098:blood supply; D013311:Streptozocin
D016326:Extracellular Matrix Proteins; D017127:Glycation End Products, Advanced; D006146:Guanidines; D011480:Protease Inhibitors; D013311:Streptozocin; D003094:Collagen; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C507081:Mmp13 protein, mouse; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline; C004479:pimagedine