VEGF resistance as a molecular basis to explain the angiogenesis paradox in diabetes mellitus.

The action of VEGF (vascular endothelial growth factor) is essential to maintain proper endothelial and vascular function. VEGF stimulates virtually all aspects of endothelial function, namely proliferation, migration, permeability and nitric oxide production and release. In addition, the action of VEGF makes the endothelium anti-apoptotic. In turn, the inhibition of VEGF action is associated with endothelial dysfunction. Likewise, endothelial dysfunction can be found in the presence of several cardiovascular risk factors, including diabetes mellitus, hypercholesterolaemia and smoking. As circulating monocytes express functionally active VEGFR-1 (VEGF receptor 1) on their surface, monocytes and the related VEGFR-1-mediated signal transduction cascades have come into focus. The function of monocytes is negatively affected by diabetes mellitus, resulting in monocyte dysfunction. More specifically, a VEGF-related signal transduction defect can be detected in monocytes isolated from diabetic individuals. This reduced monocyte response to VEGF, demonstrated by a reduced chemotactic response, can be regarded as VEGF resistance. It is based on the pre-activation of certain intracellular pathways secondary to the diabetes mellitus-related RAGE (receptor for advanced glycation end-products) activation, ROS (reactive oxygen species) activation and inhibition of PTPs (protein tyrosine phosphatases). This unspecific pre-activation of intracellular pathways represents the molecular basis of VEGF resistance in diabetes mellitus.