? The overall objective of our research is to characterize the molecular mechanisms that regulate the generation and function of blood vessels and lymphatic vessels in the skin. Our previous studies have identified vascular endothelial growth factor (VEGF) as a cytokine of central importance for normal, inflammatory and neoplastic skin angiogenesis that may also induce lymphatic vessel growth. VEGF overexpressing transgenic mice develop chronic inflammatory skin lesions that histologically resemble human psoriasis. We have also identified a critical role of VEGF-C in tumor lymphangiogenesis and lymph node metastasis. Moreover, we established a new in vitro model for the isolation of human dermal lymphatic and blood vascular endothelial cells that maintain lineage-specific differentiation even after multiple passages in vitro and that show specific responses to growth factor stimulation. We now propose experiments to test our specific hypotheses: (1) that VEGF plays a critical role in the induction and maintenance of skin inflammation, (2) that VEGF-C promotes lymphangiogenesis predominantly via activation of VEGFR-3 whereas VEGF-induced lymphangiogenesis is mediated through activation of VEGFR-2 and through indirect effects via induction of vascular hyperpermeability, and (3) that VEGF predominantly promotes skin cancer angiogenesis and organ metastasis whereas VEGF-C promotes tumor lymphangiogenesis and lymph node metastasis. Therefore, we propose to: 1. Define the importance of VEGF for cutaneous inflammation, characterizing the spontaneous and provoked, psoriasis-like skin inflammation in VEGF transgenic mice, determining the anti-inflammatory activity of VEGF receptor blockade, and identifying VEGF target genes involved in skin inflammation; 2. Define the mechanisms of VEGF versus VEGF-C-induced skin lymphangiogenesis, comparing induced lymphatic vessel formation and function in VEGF and VEGF-C transgenic mice and determining the distinct impact of VEGF and VEGF-C on gene expression and function of cultured dermal lymphatic endothelial cells; 3. Define the role of VEGF and VEGF-C in cutaneous tumor lymphangiogenesis and lymphatic versus organ metastasis in genetically fluorescent transgenic mice. ? ? At the conclusion of our studies, we will have assessed the importance of VEGF and VEGF-C for skin inflammation, angiogenesis and lymphangiogenesis, and we will have identified mechanisms that might serve as potential targets for the development of novel therapies for inflammatory skin diseases and skin cancer. ? ?
Showing the most recent 10 out of 108 publications
