uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
The role of growth factor receptor signaling for angiogenesis and vessel stability in an experimental wound healing model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Tissue vascularization during wound healing is regulated by a variety of growth factors. Although addition of a single growth factor is sufficient to induce vascularization, at least in experimental models, the question remains on how important other endogenously produced growth factors are. We have used receptor kinase inhibitors to investigate the role of FGF-, VEGF-, PDGF- and TGFb-receptor signaling for FGF-2 and PDGF-BB induced vascularization in a wound healing model based on neovascularization of a provisional matrix implanted on the chick chorioallantoic membrane. Inhibition of the PDGF pathway with Imatinib reduced FGF-2 induced angiogenesis while FGF-receptor inhibition with PD173074 did not. FGF-2 induced angiogenesis was markedly reduced when VEGF receptors were inhibited with PTK787 as was the PDGF-BB response albeit at higher inhibitor concentrations. In agreement, sequestration of VEGF with the VEGF Trap blocked both FGF-2 and PDGF-BB induced vascularization. Inactivation of TGFbR1 with SB431542 did not influence FGF-2 or PDGF-BB induced vascularization. Higher concentrations of inhibitors did not only inhibit angiogenesis but also caused established vessels to regress. While VEGF inhibition with PTK787 mainly caused micro-vessels to regress the response to PDGF receptor inhibition with Imatinib was more profound with detachment of mural cells and regression of both micro- and macro-vessels.

In summary, we found an absolute requirement of PDGF- and VEGF-receptor signaling for wound vascularization while FGF- and TGFb-receptor signalling was dispensable. Higher concentrations of growth factor inhibitors caused vessel regression which suggests a mechanism for adverse effects such as bleedings following VEGF or PDGF inhibition in clinical settings.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:uu:diva-113063OAI: oai:DiVA.org:uu-113063DiVA: diva2:289579
Available from: 2010-01-25 Created: 2010-01-25 Last updated: 2011-06-28
In thesis
1. 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

Open Access in DiVA

No full text

Authority records BETA

Gerwins, Pär

Search in DiVA

By author/editor
Gerwins, Pär
By organisation
Department of Medical Biochemistry and MicrobiologyRadiology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 471 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf