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(Circulation. 2000;102:185.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Vascular Endothelial Growth Factor-A–Induced Chemotaxis of Monocytes Is Attenuated in Patients With Diabetes Mellitus

A Potential Predictor for the Individual Capacity to Develop Collaterals

Johannes Waltenberger, MD; Juliane Lange, MD; Andrea Kranz, PhD

From the Department of Internal Medicine II, Ulm University Medical Center, Ulm, Germany.

Correspondence to Johannes Waltenberger, MD, Department of Internal Medicine II (Cardiology), Ulm University Medical Center, Robert-Koch-Str 8, D-89081 Ulm, Germany. E-mail johannes.waltenberger{at}medizin.uni-ulm.de

Background—Vascular endothelial growth factor-A (VEGF-A) acts on endothelial cells and monocytes, 2 cell types that participate in the angiogenic and arteriogenic process in vivo. Thus far, it has not been possible to identify 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 from 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 chamber. 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 patients could not be stimulated with VEGF-A (median, 91.1% of unstimulated controls; 25th and 75th percentiles, 83% and 98%; P<0.0001). In contrast, the response of monocytes to the chemoattractant formylMetLeuPhe remained intact in diabetic patients. The VEGF-A–inducible kinase activity of Flt-1, as assessed by in vitro kinase assays, remained intact in monocytes from diabetic patients. Moreover, the serum level of VEGF-A, as assessed by immunoradiometric assay, was significantly elevated in diabetic patients.

Conclusions—The cellular response of monocytes to VEGF-A is attenuated in diabetic 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 collateral formation in diabetic patients.

Key Words: collateral circulation • diabetes mellitus • signal transduction • cell movement • monocytes • endothelial growth factors

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