Dipyridamole Enhancement of Diabetic Ischemia Induced Angiogenesis

Abstract

BackgroundPeripheral Artery Disease and critical limb ischemia affect millions of Americans with an alarming increase in diabetics. There is a need for therapeutic restoration of vascular function in those affected by these diseases. We studied the hypothesis that dipyridamole could be used for angiogenic preconditioning due to its relationship with eNOS expression and activation in various tissue sites.MethodsHind limb ligations were performed in dipyridamole and control db/db diabetic mice. Serial laser Doppler blood flow measurements were taken on days 0, 3, 5, and 7. CD31, DAPI, and Ki67 immunofluorescent staining was used to evaluate vascular densities and active endothelial cell proliferation. Tissue and blood nitrite measurements were collected to confirm a rise in nitrite levels after treatment.ResultsOur experiment showed that dipyridamole significantly increased blood flow and vascular density. Blood flow levels were returned to 98.4±4.1% of pre‐ligation blood flow by day 7 in the dipyridamole dosed mice as compared to 58.2±4.5% at day 7 in the control mice. Immunofluorescent staining values were significantly increased in the ischemic limbs of dipyridamole dosed mice as compared to control mice showing that dipyridamole selectively increases ischemic hind limb vascular density and endothelial cell proliferation. Tissue nitrite levels were significantly elevated in dipyridamole dosed mice as compared to control mice.ConclusionOur results show that dipyridamole has great potential as a preconditioning and angiogenesis stimulating agent in diabetic chronic ischemia.