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Induction of neo-angiogenesis is a fundamental step in many pathological conditions. The therapeutic value of inhibiting angiogenesis is an interesting area of research in oncology, with vascular endothelial growth factor (VEGF) being the most suitable anti-angiogenic target. In the last decade a number of anti-VEGF drugs have demonstrated, especially in combination with standard chemotherapy, clinical efficacy in the treatment of different solid tumor types. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a permeability, proliferation, and migration factor, is also a maintenance and protection factor for endothelial cells, being capable of regulating multiple biological functions, i.e. the production of vasoactive mediators and the expression of components of the thrombolytic and coagulation pathways. Consequently, the disturbance of vascular homeostasis by blocking VEGF may lead to endothelial dysfunction and adverse vascular effects, such as venous and arterial thromboembolic events. In preclinical models angiogenesis and the increased expression of VEGF has been associated to altered expression of proinflammatory genes. These genes may be regulated in a biphasic manner, and it is possible that anti-VEGF therapy may disrupt a negative feedback loop that leads to potential in situ thrombus formation. Accordingly, combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was recently associated with an increased risk of thromboembolism. The present review considers the biological mechanisms and clinical impact of thromboembolic complications during anti-angiogenic treatments in cancer patients.

Vascular endothelial growth factor (VEGF) is a main regulator of blood vessel growth and plays an important role in promoting endothelial survival and maintaining the microvasculature. The kidney is a highly vascularized organ and has two important microvasculatures; glomerular and peritubular capillaries. Loss of these capillaries is strongly associated with the progression of chronic kidney disease (CKD) to end-stage renal disease. In several kidney disease animal models, VEGF expression in the kidney is decreased and administration of VEGF is protective. Recent clinical observations revealed that blocking VEGF by endogenous inhibitor (soluble Flt-1) in preeclampsia and monoclonal antibody against VEGF in cancer patients cause proteinuria and renal dysfunction. However, plasma VEGF levels in diabetic nephropathy patients are increased and blocking VEGF improved diabetic nephropathy in animal models. Increased plasma VEGF levels have been reported in CKD patients. Deleterious effects of VEGF have been demonstrated in atherosclerosis and sepsis, which are frequent complications in CKD patients. Although administrating VEGF or novel drugs that activate VEGF pathway may improve the progression of CKD, careful monitoring will be required when CKD patients have complications of diabetes, atherosclerosis or sepsis.

Neoangiogenesis, the development of new blood vessels from a pre-existing vasculature involves the migration behavior, proliferation and differentiation of endothelial cells. This process is an important aspect to both the growth and metastasis of solid tumors. In growing tumors, the development of a sufficient vascular supply is a highly complex event, which is controlled by many factors. An interaction between tumor cells, endothelial cells, macrophages, fibroblasts, and the extracellular matrix, all of which are capable of releasing factors influencing the angiogenic mechanisms is necessary for the building of new sufficient vascular structures. The increased understanding of the balance of angiogenesis and mechanisms of vascular control allowed the development of new therapeutic substances that influence that process in different ways. For example, work done over the last decade has elucidated the central role of vascular endothelial growth factor (VEGF) in the regulation of normal and pathological angiogenesis. Therefore, the blockade of VEGF signaling is currently a major part of strategies for the therapy of malignant tumors. Several studies tested neutralizing antibodies against mature VEGF protein or its isoforms, blockade of VEGF receptors by VEGF receptor antibodies, soluble VEGF receptor mutants or fusion-proteins and finally, intracellular interference with VEGF mRNA or signaling in the target cell. In this review, we present strategies and substances for the blockade of neoangiogenesis that are already in clinical use or in pre-clinical trials. Also the combination of these approaches with conventional chemotherapy or radiotherapy will be discussed.