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Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

ABSTRACT: Angiogenesis 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.

SUBMITTER: Shen CJ

PROVIDER: S-EPMC3123418 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

Shen Colette J CJ Raghavan Srivatsan S Xu Zhe Z Baranski Jan D JD Yu Xiang X Wozniak Michele A MA Miller Jordan S JS Gupta Mudit M Buckbinder Leonard L Chen Christopher S CS

Experimental cell research 20110518 13

Angiogenesis 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 intermedi ...[more]

PMID: 21640103

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Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

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Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner.

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