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

Direct link
Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization
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.
Show others and affiliations
2008 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 112, no 9, 3638-49 p.Article in journal (Refereed) Published
Abstract [en]

Vascular endothelial growth factor (VEGF)-A regulates vascular development and angiogenesis. VEGF isoforms differ in ability to bind coreceptors heparan sulfate (HS) and neuropilin-1 (NRP1). We used VEGF-A165 (which binds HS and NRP1), VEGF-A121 (binds neither HS nor NRP1), and parapoxvirus VEGF-E-NZ2 (binds NRP1 but not HS) to investigate the role of NRP1 in organization of endothelial cells into vascular structures. All 3 ligands induced similar level of VEGFR-2 tyrosine phosphorylation in the presence of NRP1. In contrast, sprouting angiogenesis in differentiating embryonic stem cells (embryoid bodies), formation of branching pericyte-embedded vessels in subcutaneous matrigel plugs, and sprouting of intersegmental vessels in developing zebrafish were induced by VEGF-A165 and VEGF-E-NZ2 but not by VEGF-A121. Analyses of recombinant factors with NRP1-binding gain- and loss-of-function properties supported the conclusion that NRP1 is critical for VEGF-induced sprouting and branching of endothelial cells. Signal transduction antibody arrays implicated NRP1 in VEGF-induced activation of p38MAPK. Inclusion of the p38MAPK inhibitor SB203580 in VEGF-A165-containing matrigel plugs led to attenuated angiogenesis and poor association with pericytes. Our data strongly indicate that the ability of VEGF ligands to bind NRP1 influences p38MAPK activation, and formation of functional, pericyte-associated vessels.

Place, publisher, year, edition, pages
2008. Vol. 112, no 9, 3638-49 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-98288DOI: 10.1182/blood-2007-12-125856ISI: 000260301800023PubMedID: 18664627OAI: oai:DiVA.org:uu-98288DiVA: diva2:174041
Available from: 2009-02-18 Created: 2009-02-18 Last updated: 2011-06-28Bibliographically approved
In thesis
1. VEGFR-2 in Endothelial Differentiation and Vascular Organization
Open this publication in new window or tab >>VEGFR-2 in Endothelial Differentiation and Vascular Organization
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The cardiovascular system is the first functional organ to develop during embryogenesis. As the embryo reaches above a certain size, passive diffusion of gases and nutrients is no longer compatible with efficient growth. During embryogenesis, endothelial progenitor cells (angioblasts) are recruited from the primitive streak mesoderm and instructed to express vascular endothelial growth factor receptor-2 (VEGFR-2). This thesis examines the roles played by VEGFR-2 in the events through which a subpopulation of embryonic stem (ES) cells differentiate into endothelial cells and form the vasculature.

We show that ES cells gene targeted for VEGFR-2 (flk1-/-) develop immature endothelial cells (ECs), precursors, when differentiated in vitro as embryoid bodies (EBs). The flk1-/- ECs are unresponsive to VEGF-stimulation and consistently fail to form vessels. However, when co-cultured with wild type ES cells in chimeric EBs, flk1-/- endothelial precursors are guided by wild type ECs to form transient, chimeric vascular structures. Use of lentivirus in an add-back approach allowed reconstitution of VEGFR-2 expression in flk1-/- ES cells, and rescue of vasculogenesis and sprouting angiogenesis. We propose that recruitment to the endothelial lineage is not dependent on VEGFR-2, although this receptor tyrosine kinase appears indispensible for EC integrity, survival and for differentation of endothelial precursors into mature ECs formating a stable vasculature.

Neuropilin-1 (NRP1) and heparan sulfate proteoglycans (HSPGs) function as co-receptors for VEGFs. The co-receptors influence, qualitatively and quantitatively, the intracellular signal relayed by VEGFR-2 but it is unclear how. We examined the contribution of NRP1 to VEGFR-2 signaling in EB cultures, in zebrafish and in mice. Only NRP1-binding VEGFs were able to promote sprouting angiogenesis and formation of properly branched vascular tubes, supported by pericytes. Downstream of VEGFR-2/NRP1 activation, we identified recruitment of p38MAPK in signal transduction regulating sprouting angiogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 48 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 322
Molecular medicine, Embryonic stem, VEGFR-2, Flk1, KDR, VEGF, vasculogenesis, angiogenesis, embryoid body, Molekylärmedicin
urn:nbn:se:uu:diva-8579 (URN)978-91-554-7133-0 (ISBN)
Public defence
2008-04-11, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
Available from: 2008-03-20 Created: 2008-03-20 Last updated: 2009-05-07Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Kjellén, Lena
By organisation
Department of Genetics and PathologyDepartment of Medical Biochemistry and Microbiology
In the same journal
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 313 hits
ReferencesLink to record
Permanent link

Direct link