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Laminin-1 promotes angiogenesis in synergy with fibroblast growth factor by distinct regulation of the gene and protein expression profile in endothelial cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
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2004 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 279, no 22, 23766-23772 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. Vol. 279, no 22, 23766-23772 p.
URN: urn:nbn:se:uu:diva-95541OAI: oai:DiVA.org:uu-95541DiVA: diva2:169801
Available from: 2007-03-08 Created: 2007-03-08Bibliographically approved
In thesis
1. Modulation of Angiogenesis by Laminins and Heparan Sulfate
Open this publication in new window or tab >>Modulation of Angiogenesis by Laminins and Heparan Sulfate
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Blood vessels transport blood with essential nutrients and oxygen to the cells in our body. In a healthy adult, formation of new vessels (angiogenesis) occurs only in case of tissue repair and growth. Physiological angiogenesis requires precise regulation of multiple signaling components, a process which is deregulated in a number of pathological conditions, such as cancer. This thesis is focused on the role of laminins, heparan sulfate proteoglycans (HSPGs) and vascular endothelial growth factor (VEGF)-A in regulation of vascular development and angiogenesis. As a model, we have used embryonic stem cells that differentiate to form blood vessels in a manner faithfully recapitulating the in vivo processes.

We show that the basement membrane (BM) protein laminin-111 promotes maturation of endothelial cells in the presence of fibroblast growth factor-2, a known endothelial cell mitogen. However, embryonic stem cells are able to differentiate into endothelial cells also in the absence of laminin deposition in the vascular BM. Sprouting angiogenesis, induced by VEGF-A, is also not strictly dependent on laminin deposition. On the other hand, in the absence of laminins, vessels are enlarged. These data suggest an important role for laminins in regulation of the vessel diameter.

We also show that HSPGs serve as coreceptors for VEGF-A to regulate vascular development. The mode of presentation of HSPGs, in cis (on the endothelial cell) or in trans (on an adjacent cell such as pericytes), is critical in regulation of VEGF receptor-2 activation and stimulation of vascular development. Binding of VEGF-A to HSPGs in trans leads to accumulation of activated VEGFR-2 in endothelial cells and to prolonged signaling. This demonstrates a potential role for HSPGs in regulation of receptor trafficking and signaling kinetics, with possible implications also for other HS-binding ligand/receptor systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 235
Molecular medicine, Embryonic stem, heparan sulfate, laminin, basement membrane, VEGFR-2, VEGF, endothelial cell, signaling, angiogenesis, vasculogenesis, embryoid body, Molekylärmedicin
urn:nbn:se:uu:diva-7666 (URN)978-91-554-6818-7 (ISBN)
Public defence
2007-03-30, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 13:15
Available from: 2007-03-08 Created: 2007-03-08Bibliographically approved

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