Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner

Journal Article · Mon Aug 01 04:00:00 EDT 2011 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2011.05.006· OSTI ID:22212159

Shen, Colette J. ^[1]; Raghavan, Srivatsan ^[1]; Xu, Zhe; Baranski, Jan D.; Yu, Xiang; Wozniak, Michele A.; Miller, Jordan S.; Gupta, Mudit ^[1]; Buckbinder, Leonard ^[2]

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1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104 (United States)
2. Pfizer Inc., CVMED Exploratory Biology, Groton, CT (United States)

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.

• OSTI ID: 22212159
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 13 Vol. 317; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANGIOGENESIS
ANIMAL TISSUES
CELL PROLIFERATION
COMPARATIVE EVALUATIONS
GENES
GROWTH FACTORS
MICE
PROLINE
SPROUTING
TYROSINE