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(Circulation. 2009;120:150-159.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Diabetes Mellitus Activates Signal Transduction Pathways Resulting in Vascular Endothelial Growth Factor Resistance of Human Monocytes

Vadim Tchaikovski, MD; Servé Olieslagers, BSc; Frank -D. Böhmer, PhD; Johannes Waltenberger, MD, PhD

From the Department of Cardiology, Maastricht University Medical Center and Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (V.T., S.O., J.W.), and Institute of Molecular Cell Biology, Medical Faculty, Friedrich Schiller University, Jena, Germany (F.-D.B.).

Correspondence to Johannes Waltenberger, MD, PhD, Department of Cardiology, University Hospital of Maastricht, P. Debyelaan 25, POB 5800, 6202 AZ Maastricht, the Netherlands. E-mail j.waltenberger{at}mumc.nl

Received August 28, 2008; accepted April 17, 2009.

Background— Monocytes are cellular components of wound repair, arteriogenesis, and atherogenesis. Vascular endothelial growth factor (VEGF)-A and placental growth factor recruit monocytes to sites of arteriogenesis via stimulation of VEGF receptor-1 (VEGFR-1). The chemotactic response of monocytes to VEGF-A is attenuated in individuals with diabetes mellitus (DM). This VEGF resistance correlates with impaired collateral growth. The aim of this study is to elucidate the molecular basis of VEGF resistance and impaired monocyte response in DM.

Methods and Results— Phosphorylation of Akt, p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) could be stimulated with either placental growth factor-1 or VEGF-A in monocytes from non-DM but not DM individuals. In contrast, formyl-methionyl-leucyl-phenylalanine caused a comparable activation of these molecules in both DM and non-DM monocytes. Baseline phosphorylation of Akt, p38, and ERK1/2 was significantly elevated in monocytes from DM compared with non-DM subjects. Of note, H₂O₂ activated Akt, p38, and ERK1/2 in non-DM monocytes ex vivo. Protein tyrosine phosphatases had stronger oxidative modifications in monocytes from DM than from non-DM individuals, which reflects functional protein tyrosine phosphatase inhibition, similar to that seen after H₂O₂ challenge. Overall, protein tyrosine phosphatase and protein tyrosine phosphatase-1B activity were reduced in DM monocytes. DM monocytes revealed higher expression of the receptor for advanced glycation end products. Stimulation with advanced glycation end products ligands resulted in activation of non-DM monocytes and inhibition of VEGFR-1–mediated chemotaxis. The elevated baseline phosphorylation/activation of Akt, p38, and ERK1/2 in DM monocytes likely causes the resistance to further stimulation with specific stimuli such as VEGF-A, revealing a molecular explanation of the DM-related signal transduction defect.

Conclusions— We propose that elevated advanced glycation end products expression and increased oxidative stress in diabetic monocytes lead to activation of VEGFR-1–related signaling pathways and to desensitization of VEGFR-1 responses. These data establish VEGF resistance as a novel molecular concept for DM-related cellular dysfunction.

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