TY - JOUR T1 - Kinin receptor agonism restores hindlimb postischemic neovascularization capacity in diabetic mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.114.219196 SP - jpet.114.219196 AU - Dorinne Desposito AU - Louis Potier AU - Catherine Chollet AU - Fernand Gobeil AU - Ronan Roussel AU - Francois Alhenc-Gelas AU - Nadine Bouby AU - Ludovic Waeckel Y1 - 2014/01/01 UR - http://jpet.aspetjournals.org/content/early/2014/11/14/jpet.114.219196.abstract N2 - Limb ischemia is a major complication of thromboembolic diseases. Diabetes worsens prognosis by impairing neovascularization. Genetic or pharmacological inactivation of the kallikrein-kinin system aggravates limb ischemia in non-diabetic animals while ACE/kininase II inhibition improves outcome. The role of kinins in limb ischemia in the setting of diabetes is not documented. We assessed whether selective activation of kinin receptors by pharmacological agonists can influence neovascularisation in diabetic mice with limb ischemia and have therapeutic effect. Selective pseudopeptide kinin B1 or B2 receptor agonists resistant to peptidase action were administered by osmotic minipumps at non-hypotensive dosage for 14 days after unilateral femoral artery ligation in mice previously rendered diabetic by streptozotocin. Comparison was made with ligatured, non-agonist treated non-diabetic and diabetic mice. Diabetes reduced neovascularisation, assessed by microangiography and histological capillary density analysis, by roughly 40%. B1 receptor agonist or B2 receptor agonist similarly restored neovascularization in diabetic mice. Neovascularization in agonist-treated diabetic mice was undistinguishable from non-diabetic mice. Both treatments restored blood flow in the ischemic hindfoot, measured by laser-doppler perfusion imaging. Macrophage infiltration increased 3 fold in the ischemic gastrocnemius muscle during B1 receptor agonist or B2 receptor agonist treatment and VEGF level 2 fold. Both treatments increased, by 50 to 100%, circulating CD45/CD11b-positive monocytes and CD34+/VEGFR2+ progenitor cells. Thus, selective pharmacological activation of B1 or B2 kinin receptor overcomes diabetes effect on postischemic neovascularization and restores tissue perfusion, through monocyte/macrophage mobilisation. Kinin receptors are potential therapeutic targets in limb ischemia in diabetes. ER -