Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner

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dc.citation.firstpage1860
dc.citation.issueNumber13
dc.citation.journalTitleExperimental Cell Research
dc.citation.lastpage1871
dc.citation.volumeNumber317
dc.contributor.authorShen, Colette J.
dc.contributor.authorRaghavan, Srivatsan
dc.contributor.authorXu, Zhe
dc.contributor.authorBaranski, Jan D.
dc.contributor.authorYu, Xiang
dc.contributor.authorWozniak, Michele A.
dc.contributor.authorMiller, Jordan S.
dc.contributor.authorGupta, Mudit
dc.contributor.authorBuckbinder, Leonard
dc.contributor.authorChen, Christopher S.
dc.date.accessioned2014-09-22T20:23:28Z
dc.date.available2014-09-22T20:23:28Z
dc.date.issued2011
dc.description.abstractAngiogenesis is regulated by both soluble growth factors and cellular interactions with the extracellular matrix (ECM). While cell adhesion via integrins has been shown to be required for angiogenesis, the effects of quantitative changes in cell adhesion and spreading against the ECM remain less clear. Here, we show that angiogenic sprouting in natural and engineered three-dimensional matrices exhibited a biphasic response, with peak sprouting when adhesion to the matrix was limited to intermediate levels. Examining changes in global gene expression to determine a genetic basis for this response, we demonstrate a vascular endothelial growth factor (VEGF)-induced upregulation of genes associated with vascular invasion and remodeling when cell adhesion was limited, whereas cells on highly adhesive surfaces upregulated genes associated with proliferation. To explore a mechanistic basis for this effect, we turned to focal adhesion kinase (FAK), a central player in adhesion signaling previously implicated in angiogenesis, and its homologue, proline-rich tyrosine kinase 2 (Pyk2). While FAK signaling had some impact, our results suggested that Pyk2 can regulate both gene expression and endothelial sprouting through its enhanced activation by VEGF in limited adhesion contexts. We also demonstrate decreased sprouting of tissue explants from Pyk2-null mice as compared to wild type mice as further confirmation of the role of Pyk2 in angiogenic sprouting. These results suggest a surprising finding that limited cell adhesion can enhance endothelial responsiveness to VEGF and demonstrate a novel role for Pyk2 in the adhesive regulation of angiogenesis.
dc.identifier.citationShen, Colette J., Raghavan, Srivatsan, Xu, Zhe, et al.. "Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner." <i>Experimental Cell Research,</i> 317, no. 13 (2011) Elsevier: 1860-1871. http://dx.doi.org/10.1016/j.yexcr.2011.05.006.
dc.identifier.doihttp://dx.doi.org/10.1016/j.yexcr.2011.05.006
dc.identifier.urihttps://hdl.handle.net/1911/77221
dc.language.isoeng
dc.publisherElsevier
dc.rightsThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier.
dc.subject.keywordangiogenesis
dc.subject.keywordcell adhesion
dc.subject.keywordgene expression
dc.subject.keywordPyk2
dc.subject.keywordVEGF
dc.titleDecreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpost-print
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