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.