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Heparin amplifies Platelet-derived growth factor (PDGF)-BB-induced PDGF alfa receptor but not PDGF beta receptor tyrosine phosphorylation in heparan sulfate-deficient cells: Effects on signal transduction and biological responses
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. (Rudbeck Laboratory)
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 Genetics and Pathology.
2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 227, no 22, 19315-19321 p.Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor (PDGF) induces mitogenic and migratory responses in a wide variety of cells, by activating specific receptor tyrosine kinases denoted the PDGF alpha- and beta-receptors. Different PDGF isoforms bind in a distinct manner to glycosaminoglycans, particularly heparan sulfate. In the present study, we show potentiation by exogenous heparin of PDGF-BB-induced PDGF alpha-receptor tyrosine phosphorylation in heparan sulfate-deficient Chinese hamster ovary (CHO) 677 cells. This effect was not seen for PDGF-AA treatment, and heparin lacked a potentiating effect on PDGF-BB stimulation of the PDGF beta-receptor. Heparin did not affect the affinity of PDGF-BB binding for the PDGF receptors on CHO 677 cells. The PDGF-BB-stimulated PDGF alpha-receptor phosphorylation was enhanced in a dose-dependent fashion by heparin at low concentration. The effect was modulated by 2-O- and 6-O-desulfation of the polysaccharide. Maximal induction of PDGF alpha-receptor tyrosine phosphorylation (6-fold) in CHO 677 cells was achieved by treatment with a heparin decasaccharide, but shorter oligosaccharides consisting of four or more monosaccharide units were also able to augment PDGF alpha-receptor phosphorylation, albeit at higher concentrations. Heparin potentiated PDGF-BB-induced activation of mitogen-activated protein kinase and protein kinase B (Akt) and allowed increased chemotaxis of the CHO 677 cells toward PDGF-BB. In conclusion, heparin modulates PDGF-BB-induced PDGF alpha-receptor phosphorylation and downstream signaling, with consequences for cellular responsiveness to the growth factor.

Place, publisher, year, edition, pages
2002. Vol. 227, no 22, 19315-19321 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-90154DOI: 10.1074/jbc.M111805200OAI: oai:DiVA.org:uu-90154DiVA: diva2:162397
Available from: 2003-02-20 Created: 2003-02-20 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Angiogenic growth factors: mechanism of action and function in vascular development
Open this publication in new window or tab >>Angiogenic growth factors: mechanism of action and function in vascular development
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mature vascular system is composed of a network of blood vessels organized into arteries, capillaries, and veins. The vessels are composed of endothelial cells surrounded by smooth muscle cells and embedded in a specialized basement membrane. The demand for oxygen during embryonal development regulates vessel formation through a process denoted vasculogenesis. These primitive vessels are further remodeled through proliferation, sprouting and migration of endothelial cells in a process denoted angiogenesis. Vasculogenesis and angiogenes are regulated by growth factors, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

To study vasculogenesis and angiogenesis, we employed differentiating embryonal stem cells (embryoid bodies). Vascularization of embryoid bodies follows a vascular pattern highly reminiscent of the in vivo pattern, leading to expression of a set of endothelial cell markers. Treatment of the embryoid bodies with different angiogenic growth factors led to distinct vascular morphologies. Expression of VEGF receptor-2 was an absolute demand for proper vascular development. PDGF-BB was shown to be potent in regulating vascular plexus formation in embryoid bodies. PDGF-BB induced capillary formation by promoting endothelial cell migration and differentiation. Hypoxia is a powerful inducer of angiogenic growth factors, such as VEGF-A, leading to angiogenesis. Hypoxia treatment induced an extensive vascular network that covered the entire embryoid body. Hypoxia-induced vascularization still occurred when VEGF receptor function was blocked, indicating that other pathway than VEGF/VEGF receptors may be critical for hypoxia-driven vessel formation.

Heparan sulfated proteoglycans (HSPGs) are present in the vascular basement membrane and are known to modulate angiogenic growth factor effects on endothelial cells in normal and pathological conditions such as tumor growth and formation of metastases. We employed heparin as an HSPG equivalent to show that PDGF-BB stimulation of PDGF a-receptor phosphorylation was augmented by heparin, resulting in increased mitogen activated protein kinase (MAPK) and protein kinase B PKB/Akt activation, and enhanced cellular migration towards PDGF-BB.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. 47 p.
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1224
Keyword
Molecular medicine, PDGF-BB, VEGF, angiogenesis, hypoxia, migration, heparin, Molekylärmedicin
National Category
Medical Genetics
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-3325 (URN)91-554-5530-1 (ISBN)
Public defence
2003-03-14, Rudbecksalen, Rudbeck Laboratory, Uppsala, 09:15
Opponent
Available from: 2003-02-20 Created: 2003-02-20 Last updated: 2018-01-13Bibliographically approved

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Spillmann, Dorothe

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