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Platelet-derived growth factor receptor-beta promotes early endothelial cell differentiation
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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2006 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 108, no 6, 1877-1886 p.Article in journal (Refereed) Published
Abstract [en]

Platelet-derived growth factor BB (PDGF-BB) has been assigned a critical role in vascular stability by promoting the recruitment of PDGF receptor-beta-expressing perivascular cells. Here we present data indicating that early hematopoietic/endothelial (hemangio) precursors express PDGFR-beta based on coexpression with CD31, vascular endothelial growth factor receptor-2, and CD41 in 2 models: mouse yolk sac (embryonic day 8 [E8]) and differentiating mouse embryonic stem cells (embryoid bodies). Expression of PDGFR-beta on hemangioprecursor cells in the embryoid bodies gradually disappeared, and, at E14, expression appeared on perivascular cells. Activation of the PDGFR-beta on the hemangioprecursors accelerated the differentiation of endothelial cells, whereas differentiation of the hematopoietic lineage was suppressed. In E9.5 yolk sacs derived from recombinant mice expressing kinase-active PDGFR-beta with an aspartic acid to asparagine (D894N) replacement in the kinase activating loop and from mice with ubiquitous expression of PDGF-BB driven by the Rosa26 locus, the number of CD41-expressing early hematopoietic cells decreased by 36% and 34%, respectively, compared with staged wild-type littermates. Moreover, enhanced vascular remodeling was evident in the Rosa26-PDGF-BB yolk sacs. We conclude that PDGFR-beta is expressed on early hemangioprecursor cells, regulating vascular/hematopoietic development.

Place, publisher, year, edition, pages
2006. Vol. 108, no 6, 1877-1886 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-19763DOI: 10.1182/blood-2006-04-014894ISI: 000240394800023PubMedID: 16690964OAI: oai:DiVA.org:uu-19763DiVA: diva2:47535
Available from: 2006-12-01 Created: 2006-12-01 Last updated: 2013-07-30Bibliographically approved
In thesis
1. Hypoxia, PDGF and VEGF in Vascular Development
Open this publication in new window or tab >>Hypoxia, PDGF and VEGF in Vascular Development
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The mechanisms behind many important aspects of blood- and lymphatic vessel formation have yet not been elucidated in detail. The primary objectives of this thesis have therefore been to study the effects of hypoxia, platelet-derived growth factor (PDGF) and vascular endothelial growth factors (VEGFs) on vascular development and function.

In conditions of low oxygen pressure, hypoxia, the survival of the organism is critically dependent on the ability to compensate for the reduced oxygen levels by promoting blood vessel growth and oxygen-independent energy production. Many direct effects of hypoxia in cells are attributed to the induction of a family of hypoxia-inducible transcription factors (HIFs) which control the expression of specific target genes. We found that capillary endothelial cells (ECs) respond to hypoxia with upregulation of genes involved in growth and remodeling of blood vessels. On the other hand, vein ECs responded to hypoxia with increased expression of genes involved in lymphatic vessel growth. Using differentiating embryonic stem (ES) cells, we have shown that hypoxia upregulates expression of VEGF receptor-3 (VEGFR-3) on blood vascular ECs. Furthermore, we have provided evidence for a critical role of VEGFR-3 in hypoxia-induced blood vessel development.

Activation of PDGF receptor-β (PDGFR-β) on early vascular progenitors in differentiating ES cells or in mice induces blood vessel differentiation, while negatively influencing early hematopoiesis. PDGFR-β expression on vascular progenitors may therefore play a role in guiding differentiation of the vascular lineages.

We have investigated the usefulness of differentiating ES cells as a model to study early lymphatic development. Administration of VEGF-C and VEGF-A induced formation of lymphatic vessel-like structures that seemed connected to the blood vasculature, supporting the general view that lymphatic ECs are derived from blood vascular ECs.

In summary, this thesis has provided new insights in the contribution of different growth factors in hematopoietic, blood- and lymphendothelial development.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 67 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 154
Cell biology, hypoxia, VEGF, VEGFR-3, PDGF, endothelial cell, embryonic stem cell, angiogenesis, lymphangiogenesis, Cellbiologi
urn:nbn:se:uu:diva-6894 (URN)91-554-6577-3 (ISBN)
Public defence
2006-06-03, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15
Available from: 2006-05-12 Created: 2006-05-12 Last updated: 2013-07-30Bibliographically approved

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Rolny, CharlotteNilsson, IngridMagnusson, PeetraJakobsson, LarsWentzel, ParriHeuchel, RainerWelsh, MichaelClaesson-Welsh, Lena
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