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Therapeutic potential of endothelial growth factors and receptors

Cancer and cardiovascular diseases are the leading causes of morbidity and mortality in the developed countries. Current cardiovascular and cancer therapies are often insufficient, unsuccessful or not suitable for all patients, thus novel therapies are urgently needed. Inhibition of angiogenesis is already used in the clinics, but with limited success. On the other hand, stimulation of the growth of blood vessels, angiogenesis, and the stimulation of arteriogenesis has been unsuccessfully tried for the treatment of tissue ischemia in humans. The elucidation of disease-related functions of endothelial growth factors and their signal transduction in cancer and cardiovascular disease should help in development of improved therapy for these diseases. Possible new therapy requires solid knowledge of the biology of vascular endothelial growth factors, angiopoietins, angiogenesis and lymphangiogenesis.

Growth factor mechanisms operating in angiogenesis and lymphangiogenesis

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Vascular endothelial growth factors (VEGFs) are major regulators of blood and lymphatic vessel development and growth. VEGFs stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases and neuropilin (NRP) coreceptors in endothelial cells (Figure 1).

VEGF is induced in tissue hypoxia, for example in embryos and in tumors. VEGF-C and VEGF-D can directly induce lymphangiogenesis by activating VEGFR-3 in lymphatic endothelial cells. It binds VEGFR-1 and VEGFR-2 in nearby endothelial cells initiating the process of new vessel growth. Although antibodies that block VEGF have been successfully used in tumor therapy, attempts to use VEGF for proangiogenic therapy in tissue ischemia have been hampered by its property to increase vascular permeability and promote angioma-like formation.

VEGF-B has remained rather enigmatic since its identification more than 15 years ago. VEGF-B expression levels are highest in tissues that need high levels of energy metabolism. Mice deficient in VEGF-B are viable and fertile and display only a mild phenotype in some mouse strains. Supraphysiological VEGF-B levels obtained by adenoviral transfection induce capillary enlargement in the heart, but the ability of VEGF-B to promote angiogenesis directly is at best very weak. However, based on new findings on VEGF-B by the Alitalo group, a breakthrough in the therapy of cardiovascular ischemia has become closer. VEGF-B may also play an important role in the development of type 2 diabetes and metabolic disease.

In addition to the VEGFs, the angiopoeitin growth factors (ANG, also termed ANGPT) and their endothelial TIE receptors are significant regulators of both lymphatic and blood vessels. Recently, much interest has focused on the function of the ANG-TIE system in a number of diseases, including sepsis, acute respiratory distress syndrome, diabetes and cancer, among others, and on the possibilities to target the ANG-TIE system in the various diseases.

Research program

A/wp-content/uploads/2013/04/358-1024-14-4-5-40x-1-rgd_PS_120x120px.pngAngiopoietin growth factors
The angiopoietin growth factors (Ang, ANGPT) and their Tie receptors are key signaling molecules in controlling the various functions of the vasculature. Scientists at WRI have identified growth factor mechanisms regulating signaling via the Ang-Tie system, and unraveled how this system may be modulated to inhibit tumor metastasis.
/wp-content/uploads/2013/04/VEGFCR2complex_120x120px.pngStructure of vascular growth factor-receptor complexes
Vascular endothelial growth factor (VEGF) receptors are among the major mediators of both angiogenesis and lymphangiogenesis in development and in disease. Scientists at WRI have determined the crystal structures of the VEGF-C – VEGFR-2 complex and of the VEGF-D growth factor, revealing structural determinants mediating specificity of ligand-receptor interactions.
/wp-content/uploads/2013/04/GZ_4_120x120px.pngVEGFRs in vascular development and disease
Vascular Endothelial Growth Receptors (VEGFRs) are principal regulators of embryonic, postnatal and pathological angiogenesis. Using state of the art genetic models, scientists at WRI have identified novel functions for VEGFR-3 in blood vessel development and have elucidated some of the mechanisms by which VEGFR-3 controls angiogenic signaling.
/wp-content/uploads/2013/04/Sydan_2_120x120px.pngVascular growth factors regulating coronary artery growth
Vascular endothelial growth factor B (VEGF-B) is one of the less well understood endothelial growth factors that specifically binds to VEGF receptor-1 (VEGFR-1). Scientists at WRI have recently found that the VEGF-B growth factor can induce hypertrophy, and the growth of coronary blood vessels, thus opening possibilities for therapeutic use of VEGF-B in cardiovascular diseases.
/wp-content/uploads/2013/04/AdiposeTissueStaining_120x120px.pngLymphatic vessels in obesity and cardiovascular disease
Scientists at WRI have made seminal and clinically translatable discoveries in the field of lymphatic biology. Recent discoveries unexpectedly link lymphatic vessel malfunction to obesity and cardiovascular disease processes, such as thrombosis and atherosclerosis.
/wp-content/uploads/2013/04/100226-Cholesterol-crystals-confocal-KR_120x120px.pngLipoprotein particles and their modification
Chronic inflammation is the major driving force in atherogenesis. In the arterial wall, modified LDL particles trigger and maintain inflammation, while HDL particles exert anti-atherogenic actions. Among the inflammatory cells in atherosclerotic lesions, activated mast cells are found. The mast cells secrete a vast array of critical proinflammatory mediators. Expand
The scientists at the WRI have uncovered mechanisms by which activated mast cells participate in the development of the lesions. In addition, they have delineated the roles of several types of modified LDL and HDL in the initiation and progression of atherogenesis. They also proposed novel pathways in the molecular pathogenesis of aortic stenosis to lay scientific foundations for clinical success of future pharmacotherapies of this disease.