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Endocan is a VEGF-A and PI3K regulated gene with increased expression in human renal cancer
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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2007 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 313, no 7, 1285-1294 p.Article in journal (Refereed) Published
Abstract [en]

An in vitro model of VEGF-A-induced angiogenesis was used to generate transcription profiles of human microvascular endothelial cells. Microarray analysis showed increased transcription of genes known to regulate angiogenesis, but also genes that previously have not been firmly associated with angiogenesis such as endocan, pinin, plakophilin, phosphodiesterase 4B and gelsolin. Increased endocan mRNA levels in response to VEGF-A in endothelial cells and in human renal cancer have previously been reported. We now show increased endocan protein levels in VEGF-A treated endothelial cells and in human renal clear cell carcinoma. Increased protein expression was observed both in tumor cells and in a subset of tumor vessels, while expression in normal kidney tissue was low. VEGF-A seemed to be a specific inducer of endocan transcription since FGF-2, PDGF-BB, HGF/SF and EGF did not alter expression levels. Inhibition of PI3K with LY294002 caused a 12-fold increase in endocan transcription suggesting a repressive function of PI3K. In contrast inhibition of Src or MEK, which are signaling pathways activated by VEGF-A, did not influence basal or VEGF-A-induced endocan levels. In conclusion our study shows that, among angiogenic growth factors, VEGF-A is a specific inducer of endocan transcription which is translated into increased protein levels in VEGF-A treated endothelial cells. Increased endocan protein expression in human renal cancer suggests a role in tumor growth.

Place, publisher, year, edition, pages
2007. Vol. 313, no 7, 1285-1294 p.
Keyword [en]
Angiogenesis, Endocan, Microarray, Renal tumor, Vascular endothelial growth factor, Endothelium
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-11015DOI: 10.1016/j.yexcr.2007.01.021ISI: 000245681800001PubMedID: 17362927OAI: oai:DiVA.org:uu-11015DiVA: diva2:38783
Available from: 2007-06-14 Created: 2007-06-14 Last updated: 2017-12-11Bibliographically 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)
Opponent
Supervisors
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2009-05-13Bibliographically approved
2. The Roles of Growth Factor Interactions and Mechanical Tension in Angiogenesis
Open this publication in new window or tab >>The Roles of Growth Factor Interactions and Mechanical Tension in Angiogenesis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis, the formation of new blood vessels from preexisting ones through creation of new vessel branch points by sprouting or vessel splitting, is an important part of tissue growth in both physiological processes like wound healing and pathological conditions such as cancer. Growth factors like VEGF-A, FGF-2 and PDGF-BB are involved in both types of angiogenesis.

Screening for genes regulated by VEGF-A stimulation in endothelial cells revealed up regulation of the endothelial cell specific glycoprotein endocan. Endocan itself did not stimulate angiogenesis. VEGF was a specific inducer since FGF-2, PDGF-BB, HGF and EGF did not alter expression. The signaling molecule PI3K was a negative regulator of endocan expression. Endocan was expressed in tumor cells and vessels, suggesting that although endocan did not directly regulate angiogenesis it can serve as a marker for angiogenic tumors.

In two models of wound healing angiogenesis, the chick extra-embryonal CAM assay and the mouse cornea assay, we observed that blood vessels grew into avascular areas as functional mural cell covered loops by elongation of preexisting vessels. Loop formation was simultaneous with contraction of the avascular matrix mediated by proto/myofibroblasts. Reducing the contractibility of the stroma reduced vessel ingrowth, showing that contraction was necessary for mediating and directing growth of the vascular loops. These findings suggest a model for biomechanical regulation of vascularization that is complementary to sprouting angiogenesis which is guided by gradients of growth factors.

In defining the role of growth factors, in the CAM assay, we found that FGF-2 and PDGF-BB induced vessel ingrowth, while VEGF-A, EGF and HGF did not. TGF-beta reduced the effect of FGF-2. By use of specific receptor kinase inhibitors we found an absolute requirement VEGF- and PDGF-receptor activity for vascularization while FGF- and TGF-beta-receptor function was dispensable. This suggests that functional VEGF- and PDGF-receptors are needed for vessel elongation.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 519
Keyword
angiogenesis, myofibroblast, wound healing, VEGF, FGF, PDGF, endocan, endothelial cell, vascularization
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:uu:diva-113238 (URN)978-91-554-7717-2 (ISBN)
Public defence
2010-03-12, C8:301, BMC, Biomedical Center Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2010-02-18 Created: 2010-01-26 Last updated: 2010-02-18Bibliographically approved

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Mellberg, SofieDimberg, AnnaPetersson, LudvigBotling, JohanAmeur, AdamKomorowski, JanGerwins, Pär

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