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Platelet-derived growth factor receptor-β (D849V) activating mutation promotes vascular development and angiogenic sprouting by differentiating embryonic stem cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-93160OAI: oai:DiVA.org:uu-93160DiVA: diva2:166549
Available from: 2005-05-12 Created: 2005-05-12 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Fibroblast Growth Factor Receptor-1 Function in Vasculo- and Angiogenesis
Open this publication in new window or tab >>Fibroblast Growth Factor Receptor-1 Function in Vasculo- and Angiogenesis
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During development of the mammalian embryo, spatial and temporal expression of fibroblast growth factors (FGFs) and their cognate receptors are vital in the regulation of a number of patterning processes. Inappropriate or decreased expression leads to severe malformations and even embryonic death. The objectives of this thesis have been to evaluate the usefulness of differentiating embryonic stem (ES) cells as a model to study FGF and FGF receptors in endothelial and hematopoietic cell function in vitro and in vivo, and the effect of an activating mutation in the platelet-derived growth factor receptor-β (PDGFR-β) on endothelial cells and vessel formation.

Aggregates of differentiating ES cells, denoted embryoid bodies, faithfully recapitulate many developmental processes. Embryoid bodies cultured in fetal calf serum spontaneously develop cardiomyocytes and endothelial cells. The endothelial cells organize into lumen-containing vessels carrying erythroblasts. Administration of FGF or vascular endothelial growth factor (VEGF)-A promotes development of specific vascular phenotypes. About 20% of endothelial cells in embryoid bodies and teratomas express FGFR-1, and these FGFR-1-expressing endothelial cells are mitogenically active in the absence of exogenous stimuli and respond to VEGF-A to the same extent as endothelial cells lacking FGFR-1 expression. FGFR-1 deficiency leads to arrest in hematopoietic differentiation, whereas endothelial cell development is enhanced. As a consequence, teratomas derived from ES cells lacking FGFR-1 expression display vessels composed of a double layer of endothelial cells. The hyperactivity of endothelial cells derived from FGFR-1-deficient ES cells is suggested to be due to hyperactivity of VEGF receptor-2, as well as to loss of negative regulators of angiogenesis, such as interleukin-4.

Mutation of platelet-derived factor receptor-β (PDGFR-β) to replace D849 in the activating loop in the kinase domain with V leads to ligand-independent kinase activity, increased basal signal transduction, and enhanced expression of VEGF-A as well as VEGFR-2. As a result, endothelial cell sprouts covered with pericyte-like cells are formed in a VEGF-A/VEGFR-2 dependent manner in ES cells expressing the mutated PDGFR-β.

In conclusion, embryoid bodies represent a high-quality model for the study of growth factor-regulated vascular development and sprouting angiogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 47 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 47
Pathology, FGF, FGFR-1, VEGFR-2, PDGFR-β, endothelial cells, embryonic stem cell, angiogenesis, hematopoiesis, Patologi
National Category
Cell and Molecular Biology
urn:nbn:se:uu:diva-5824 (URN)91-554-6272-3 (ISBN)
Public defence
2005-06-03, Rudbecksalen, Rubecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2005-05-12 Created: 2005-05-12Bibliographically approved

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