Regulation of Angiogenesis and Lymphangiogenesis by Endothelial Cell Signaling Molecules

Show simple item record

dc.contributor Helsingin yliopisto, lääketieteellinen tiedekunta, biolääketieteen laitos fi
dc.contributor Helsingfors universitet, medicinska fakulteten, biomedicinska institutionen sv
dc.contributor University of Helsinki, Faculty of Medicine, Institute of Biomedicine, Research Program Unit en
dc.contributor.author Zheng, Wei fi
dc.date.accessioned 2013-11-27T09:45:57Z
dc.date.available 2013-12-03 fi
dc.date.available 2013-11-27T09:45:57Z
dc.date.issued 2013-12-13 fi
dc.identifier.uri URN:ISBN:978-952-10-9567-2 fi
dc.identifier.uri http://hdl.handle.net/10138/42171
dc.description.abstract Blood vessels deliver nutrients and oxygen to tissues, whereas lymphatic vessels collect interstitial fluid and absorb lipids. Both types of vessels are involved in immune surveillance. Malformation or malfunction of either vasculature is closely associated with various diseases. Although the molecular mechanisms regulating the growth, development and function of these vessels have begun to emerge in recent decades, many questions remain. This study aimed to understand if and how the growth of new blood and lymphatic vessels (angiogenesis and lymphangiogenesis, respectively) is regulated by the endothelial signaling molecules BMX, VEGFR-3, notch 1 and angiopoietin-2. BMX, a non-receptor tyrosine kinase, is upregulated in some types of cancer and promotes cell survival, migration and proliferation. Under physiological conditions, it is also highly expressed in blood endothelial cells (BECs). Thus, we hypothesized that BMX might contribute to tumor growth by promoting tumor angiogenesis. Using multiple tumor implantation and spontaneous tumor models in Bmx gene-deleted mice, we found that tumor angiogenesis and growth were significantly reduced in the absence of BMX. Conversely, when BMX was overexpressed in epithelial keratinocytes, chemical carcinogen led to increased tumor angiogenesis and growth. VEGFR-3 is a growth factor receptor on the surface of endothelial cells (ECs). Here, we characterized a blocking antibody that inhibits VEGFR-3 signaling by a novel mechanism. In contrast to conventional blocking antibodies that prevent ligand-receptor binding, this new antibody inhibited dimerization of two identical VEGFR-3 molecules, thereby impairing signaling activation and sprouting of lymphatic endothelial cells (LECs). These inhibitory effects persisted even at ligand concentrations so high that conventional blocking antibodies were no longer effective. Importantly, concurrent treatment with both types of antibodies yielded combined additive benefits. Notch signaling regulates angiogenic sprouting. We found in this study that Notch inhibitors enhance VEGF-induced lymphatic sprouting in 3-dimensional EC sprouting assays in vitro. In vivo, VEGF alone induced only lymphatic dilation but not sprouting. However, concomitant treatment with a Notch inhibitor induced both vascular events. In addition, a mosaic-sprouting assay showed that Notch signaling also determined the fates of tip/stalk cells (the cell leading a vessel sprout and the following cells, respectively) during lymphatic sprouting. Angiopoietin-2 (Ang2) is an endothelial growth factor required for proper lymphatic remodeling during development, but the exact mechanisms of this process have previously remained unclear. In contrast to the zipper-like pattern of cell-cell junctions (zippers) in collecting lymphatic vessels, mature lymphatic capillaries have a distinct pattern of button-like junctions (buttons), which transform from zippers during development. We found in this study that Ang2 is indispensable for such transformation of the junctional patterns during embryogenesis. At the molecular level, Ang2 is required for phosphorylation of the adherens junction marker vascular endothelial cadherin (VE-cadherin) at the tyrosine residue 685. Ang2 blocking antibody treatment of mouse neonates disrupted cell-cell junctions in the mesenteric lymphatic vessels, causing leakage of chyle (milky fluids containing fat droplets and lymph). Ang2 blockade also inhibited lymphatic valve formation and maturation and resulted in abnormal smooth muscle recruitment. Together, these results provide new insights into the molecular mechanisms of angiogenesis and lymphangiogenesis. Elucidation of these mechanisms is important in developing new drugs for the treatment of vessel-related diseases, including cancer and pathological inflammation. Moreover, these findings introduce the reorganization of cell-cell junctions as a novel parameter for evaluating lymphatic development and call for future research into this new field. en
dc.description.abstract Not available fi
dc.language.iso en fi
dc.rights Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty. fi
dc.rights This publication is copyrighted. You may download, display and print it for Your own personal use. Commercial use is prohibited. en
dc.rights Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden. sv
dc.subject biomedicine fi
dc.title Regulation of Angiogenesis and Lymphangiogenesis by Endothelial Cell Signaling Molecules en
dc.type.ontasot Väitöskirja (artikkeli) fi
dc.type.ontasot Doctoral dissertation (article-based) en
dc.type.ontasot Doktorsavhandling (sammanläggning) sv
dc.ths Alitalo, Kari fi
dc.opn Kitajewski, Jan fi
dc.type.dcmitype Text fi

Files in this item

Files Size Format View

There are no files associated with this item.

This item appears in the following Collection(s)

Show simple item record