Impaired revascularization in a mouse model of type 2 diabetes is associated with dysregulation of a complex angiogenic-regulatory network

Objective - Diabetes is a risk factor for the development of cardiovascular diseases associated with impaired angiogenesis or increased endothelial cell apoptosis. Methods and Results - Here it is shown that angiogenic repair of ischemic hindlimbs was impaired in Lepr db/db mice, a leptin receptor-deficient model of diabetes, compared with wild-type (WT) C57BL/6 mice, as evaluated by laser Doppler flow and capillary density analyses. To identify molecular targets associated with this disease process, hindlimb cDNA expression profiles were created from adductor muscle of Lepr db/db and WT mice before and after hindlimb ischemia using Affymetrix GeneChip Mouse Expression Set microarrays. The expression patterns of numerous angiogenesis-related proteins were altered in Lepr db/db versus WT mice after ischemic injury. These transcripts included neuropilin-1, vascular endothelia growth factor-A, placental growth factor, elastin, and matrix metalloproteinases implicated in blood vessel growth and maintenance of vessel wall integrity. Conclusion - These data illustrate that impaired ischemia-induced neovascularization in type 2 diabetes is associated with the dysregulation of a complex angiogenesis-regulatory network. © 2005 American Heart Association, Inc.