Kinin receptor agonism restores hindlimb postischemic neovascularization capacity in diabetic mice.
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 nondiabetic animals, whereas angiotensin I-converting enzyme/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 neovascularization in diabetic mice with limb ischemia and have a therapeutic effect. Selective pseudopeptide kinin B1 or B2 receptor agonists resistant to peptidase action were administered by osmotic minipumps at a nonhypotensive dosage for 14 days after unilateral femoral artery ligation in mice previously rendered diabetic by streptozotocin. Comparison was made with ligatured, nonagonist-treated nondiabetic and diabetic mice. Diabetes reduced neovascularization, assessed by microangiography and histologic 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 indistinguishable from nondiabetic 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 vascular endothelial growth factor (VEGF) level increased 2-fold. Both treatments increased, by 50-100%, circulating CD45/CD11b-positive monocytes and CD34(+)/VEGFR2(+) progenitor cells. Thus, selective pharmacological activation of B1 or B2 kinin receptor overcomes the effect of diabetes on postischemic neovascularization and restores tissue perfusion through monocyte/macrophage mobilization. Kinin receptors are potential therapeutic targets in limb ischemia in diabetes.
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Dorinne
D
Desposito
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Louis
L
Potier
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Catherine
C
Chollet
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Fernand
F
Gobeil
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Ronan
R
Roussel
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Francois
F
Alhenc-Gelas
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.).
Nadine
N
Bouby
Institut National de la Sante et de la Recherche Medicale U1138, Université Paris Descartes, and Université Pierre et Marie Curie, Paris, France (D.D., L.P., C.C., R.R., F.A.-G., N.B., L.W.); Université Paris Diderot, and Diabétologie-Endocrinologie-Nutrition, DHU FIRE, Hôpital Bichat, AP-HP, Paris, France (L.P., R.R.); and Department of Pharmacology, University of Sherbrooke, Sherbrooke, Quebec, Canada (F.G.) ludovic.waeckel@crc.jussieu.fr.
Ludovic
L
Waeckel
D000818:Animals; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D016234:Kallikrein-Kinin System / Q000187:drug effects; D017078:Laser-Doppler Flowmetry; D008297:Male; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D043783:Receptor, Bradykinin B1 / Q000819:agonists*; D043782:Receptor, Bradykinin B2 / Q000819:agonists*; D012039:Regional Blood Flow / Q000187:drug effects; D013311:Streptozocin / Q000494:pharmacology
D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C583125:bradykinin, (Hyp(3)-Thi(5)-(N)Chg(7)-Thi(8))-bradykinin; C583124:bradykinin, Sar-Lys-(Hyp(3)-Igl(5)-Phe(8))-desArg(9)-; D013311:Streptozocin; D001920:Bradykinin