VEGFR3 and Notch signaling in angiogenesis

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Julkaisun nimi: VEGFR3 and Notch signaling in angiogenesis
Tekijä: Zarkada, Georgia
Muu tekijä: Helsingin yliopisto, lääketieteellinen tiedekunta, biolääketieteen laitos
Opinnäytteen taso: Väitöskirja (artikkeli)
Tiivistelmä: Blood and lymphatic vessels form extensive networks throughout the body, which function in order to deliver oxygen and nutrients to the tissues, to remove extravasated fluid and to absorb dietary lipids. The formation of new blood and lymphatic vessels (termed angiogenesis and lymphangiogenesis) is critical during embryonic development and in the adult, and is regulated by multiple signaling pathways. Vascular Endothelial Growth Factors (VEGFs) and their receptors (VEGFRs), as well as the Notch signaling system, are key governors of blood and lymphatic endothelial cell fate, and regulate angiogenesis and lymphangiogenesis in health and disease. Despite the numerous recent advances in the field of vascular biology, many steps in the complex processes of angiogenesis and lymphangiogenesis remain unclear. In this study we investigated the role of VEGFR3 signaling in blood endothelial cells, tip cell specification, as well as the interplay of the receptor with the VEGFR2 and the Notch signaling pathways during angiogenesis. VEGFR3 is a tyrosine kinase receptor that is mainly expressed in lymphatic endothelial cells in the adult. We observed VEGFR3 expression in sprouts that guide the blood vascular endothelium in angiogenic conditions. VEGFR3 blockade with a monoclonal antibody displayed synergistic properties with simultaneous VEGFR2 targeting in reducing angiogenesis and inhibiting tumor growth. Furthermore we found that Notch signaling suppresses VEGFR3 expression in endothelial cells, identifying VEGFR3 as a novel tip cell marker, which is normally repressed by Notch activation. In the next step we employed a combination of genetic and in vitro models to show that loss of VEGFR3 results in a hypervascular phenotype, accompanied by loss of Notch signaling. VEGFR3 could be stimulated by VEGFC and activate Notch in blood endothelial cells. Our results point towards a mechanism where VEGFC produced by macrophages at the vascular front acts via VEGFR3 to activate Notch and turn tip into stalk cells; thus promoting the formation of stable vascular loops. Furthermore we identified the transcription factor FOXC2 as the downstream target of the VEGFC/VEGFR3/Notch signaling cascade. These data reinforce the idea that VEGFR3 has two distinct signaling modalities, one ligand-dependent and one ligand-independent, and that different perturbations in VEGFR3 expression and function result in diverse vascular phenotypes. Subsequently we investigated the interplay of VEGFR2 and VEGFR3 in postnatal angiogenesis and lymphangiogenesis, using a genetic approach of conditional mutagenesis. Various combinations of genetic ablation of VEGFRs and pharmacological inhibition of Notch showed that VEGFR2 is irreplaceable during sprouting angiogenesis, also in endothelial cells with low Notch signaling, and that it acts upstream of VEGFR3 expression in angiogenic settings. On the other hand VEGFR3 suppressed VEGFR2 expression in a negative feedback loop. Finally we employed for the first time lymphatic endothelial specific deletion of VEGFRs in postnatal conditions and found no significant role for VEGFR2 in lymphatic vessel growth and remodeling, while VEGFR3 signaling was indispensable. Our results unravel previously unknown roles for VEGFR3 in sprouting angiogenesis and provide new insight into the signaling cross-talk of the receptor with other important regulators of blood vessel development. Increasing our understanding of the molecular mechanisms underlying this process is crucial in order to comprehend the pathophysiology of angiogenesis-related diseases, characterized by excessive or insufficient blood vessel growth, and promote the emergence of novel angiogenic therapies.Not available
URI: URN:ISBN:978-952-10-9997-7
Päiväys: 2014-08-08
Avainsanat: biomedicine
Tekijänoikeustiedot: Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.


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