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Transcriptional profiling reveals a critical role for tyrosine phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2009 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 5, 1490-1502 p.Article in journal (Refereed) Published
Abstract [en]

To define molecular events accompanying formation of the 3-dimensional   (3D) vascular tube, we have characterized gene expression during vascular endothelial growth factor (VEGF)-induced tubular morphogenesis of endothelial cells. Microarray analyses were performed comparing gene induction in growth-arrested, tube-forming endothelial cells harvested from 3D collagen cultures to that in proliferating endothelial cells cultured on fibronectin. Differentially expressed genes were clustered and analyzed for specific endothelial expression through publicly  available datasets. We validated the contribution of one of the identified genes vascular endothelial protein tyrosine phosphatase   (VE-PTP), to endothelial morphogenesis. Silencing of VE-PTP expression was accompanied by increased VEGF receptor-2 (VEGFR2) tyrosine  phosphorylation and activation of downstream signaling pathways. The  increased VEGFR2 activity promoted endothelial cell cycle progression,   overcoming the G(0)/G(1) arrest associated with organization into   tubular structures in the 3D cultures. Proximity ligation showed close   association between VEGFR2 and VE-PTP in resting cells. Activation of   VEGFR2 by VEGF led to rapid loss of association, which was resumed with   time in parallel with decreased receptor activity. In conclusion, we   have identified genes, which may serve critical functions in formation  of the vascular tube. One of these, VE-PTP, regulates VEGFR2 activity  thereby modulating the VEGF-response during angiogenesis.-Mellberg, S.,  Dimberg, A., Bahram, F., Hayashi, M., Rennel, E., Ameur, A., Westholm,   J. O., Larsson, E., Lindahl, P., Cross, M. J., Claesson-Welsh, L.   Transcriptional profiling reveals a critical role for tyrosine   phosphatase VE-PTP in regulation of VEGFR2 activity and endothelial cell morphogenesis. FASEB J. 23, 1490-1502 (2009)

Place, publisher, year, edition, pages
2009. Vol. 23, no 5, 1490-1502 p.
Keyword [en]
angiogenesis, gene expression, PTPRB, HPTP beta, signal transduction
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97893DOI: 10.1096/fj.08-123810ISI: 000266651700025PubMedID: 19136612OAI: oai:DiVA.org:uu-97893DiVA: diva2:172994
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Molecular Regulation of Angiogenesis
Open this publication in new window or tab >>Molecular Regulation of Angiogenesis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, de novo formation of blood vessels from the pre-existing vasculature, is crucial in embryo development, and in processes in the adult such as wound healing and ovulation. Angiogenesis is also involved in pathological conditions such as cancer and chronic inflammatory diseases, which are propagated by dysregulated, excess angiogenesis. On the other hand, lack of functional vessels and poor blood flow is a major problem in myocardial and peripheral ischemia. A detailed understanding of the molecular mechanisms underlying angiogenesis is of vital importance for the development of drugs to regulate angiogenesis. The aim of this thesis has been to identify genes involved in regulation of angiogenesis.

We have investigated gene expression over time in endothelial cells (ECs), using different in vitro models. We show that the proteoglycan endocan is upregulated in ECs invading a fibrin matrix in response to vascular endothelial growth factor (VEGF)-A. There was increased expression of endocan in renal tumour cells and tumour vessels compared to normal renal tissues, indicating that endocan might have a role in tumour growth and tumour angiogenesis.

We also show that vascular endothelial protein tyrosine phosphatase (VE-PTP) is induced in ECs during differentiation into vessel structures in a three dimensional collagen matrix. Silencing of VE-PTP disrupts vessel formation and increases the activity of VEGF receptor-2 (VEGFR-2) and downstream signalling, leading to increased EC proliferation. This presents a possible mechanism for the failure of vessel formation, as EC morphogenesis requires growth arrest of the cells. We also show that VE-PTP and VEGFR-2 are closely associated in resting ECs. VEGF-A stimulation leads to rapid loss of association, coinciding with increased phosphorylation of VEGFR-2.

The function of VE-PTP in vivo was investigated using the zebrafish model. We demonstrate specific expression of a zebrafish VE-PTP orthologue (zVE-PTP) in the developing vasculature. Silencing of zVE-PTP leads to defective vessel sprouting and branching, indicating a critical role for zVE-PTP in development of the zebrafish vasculature.

In conclusion, this thesis presents gene regulation during endothelial cell morphogenesis and details the expression pattern of endocan and the function of VE-PTP in regulation of VEGFR-2-driven angiogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 406
Keyword
endothelial morphogenesis, VEGFR-2, protein tyrosine phosphatase, VE-PTP, PTPRB, endocan, ESM-1, angiogenesis
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-9418 (URN)978-91-554-7366-2 (ISBN)
Public defence
2008-12-18, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:00 (English)
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Supervisors
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2009-05-13Bibliographically approved

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Dimberg, AnnaClaesson-Welsh, Lena

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