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Hypoxia regulates vascular development in embryoid bodies via vascular growth factor-dependent and-independent pathways
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-90153OAI: oai:DiVA.org:uu-90153DiVA: diva2:162396
Available from: 2003-02-20 Created: 2003-02-20 Last updated: 2010-01-13Bibliographically 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.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1224
Molecular medicine, PDGF-BB, VEGF, angiogenesis, hypoxia, migration, heparin, Molekylärmedicin
National Category
Medical Genetics
Research subject
Molecular Medicine
urn:nbn:se:uu:diva-3325 (URN)91-554-5530-1 (ISBN)
Public defence
2003-03-14, Rudbecksalen, Rudbeck Laboratory, Uppsala, 09:15
Available from: 2003-02-20 Created: 2003-02-20Bibliographically approved

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