Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus - A potential predictor for theindividual capacity to develop collaterals

Background-Vascular endothelial growth factor-A (VEGF-A) acts on endothelia l cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identif y differences in individual responses to VEGF-A stimulation because of the lack of an ex vivo assay. Methods and Results-We report a chemotaxis assay using isolated monocytes f rom individual diabetic patients and from healthy, age-matched volunteers. The chemotactic response of individual monocyte preparations to VEGF-A, as mediated via Flt-1, was quantitatively assessed using a modified Boyden cha mber. Although the migration of monocytes from healthy volunteers could be stimulated with VEGF-A (1 ng/mL) to a median of 148.4% of the control value (25th and 75th percentiles, 136% and 170%), monocytes from diabetic patien ts could not be stimulated with VEGF-A (median, 91.1% of unstimulated contr ols; 25th and 75th percentiles, 83% and 98%; P<0.0001). In contrast, the re sponse of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A-inducible kinase activity of Flt-1, as ass essed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiom etric assay, was significantly elevated in diabetic patients. Conclusions-The cellular response of monocytes to VEGF-A is attenuated in d iabetic patients because of a downstream signal transduction defect. These data suggest that monocytes are important in arteriogenesis and that their ability to migrate might be critical to the arteriogenic response. Thus, we resolved a fundamental mechanism involved in the problem of impaired colla teral formation in diabetic patients.