Molecular mechanisms of VEGF-mediated angiogenesis and vascular permeability

Sammanfattning: Angiogenesis, sprouting of new capillaries from pre-existing blood vessels, is a tightly regulated multi-step process. One of the key mediators in this process is the Vascular Endothelial Growth Factor (VEGF). Many tumors express high levels of VEGF and pathological angiogenesis is considered a hallmark of malignant tumor growth. Tumor vessels are often leaky and prone to hemorrhaging, most likely due to the vascular permeabilityenhancing effect of VEGF, a feature that distinguishes it from other angiogenic proteins. In this thesis, the focus has been on members of the VEGF-family, and their role in angiogenesis and vascular permeability. We have shown that VEGF-C is angiogenic in addition to its known effects on lymph vessel growth (lymphangiogenesis) and vascular permeability. In capillaries, vascular leakage induced by VEGF and VEGF-C was mostly mediated via fenestrac, small pore-like openings in the endothelial cells. In contrast, Fibroblast Growth Factor-2 (FGF-2), another well characterized angiogenic protein, did not induce any vascular permeability and FGF-2-induced blood vessels did not exhibit any fenestrae. VEGF-induced vascular permeability and formation of fenestrae could be reduced by inhibition of Rac, a protein involved in reorganization of the actin cytoskeleton. Rac inhibition also affected angiogenesis, but to a lesser degree than vascular leakage. Thus, the signaling pathways leading to angiogenesis and vascular permeability in response to VEGF are in part separated. Another member of the VEGF-family, Placental Growth Factor (P1GF) could also modulate VEGF- induced angiogenesis. When VEGF and P1GF-1 were coexpressed in tumor cells, they formed heterodimers that were functionally inactive, thus effectively depleting the pool of available bioactive VEGF homodimers and hence angiogenesis and tumor growth were reduced. In summary, the angiogenic and vascular permeability-stimulating effects of members of the VEGF-family can be modulated in at least two ways, formation of inactive heterodimers and interfering with the intracellular signaling. This could have conceptual implications in the treatment of tumor growth and other diseases characterized by pathological vascular permeability.