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Decreased cell adhesion promotes angiogenesis in a Pyk2-dependent manner
Colette J Shen1, Srivatsan Raghavan, Zhe Xu
1Department of Bioengineering, University of Pennsylvania, 210 South 33rd Street, Philadelphia, PA 19104, USA.
Experimental Cell Research
|June 7, 2011
Summary
Limited cell adhesion to the extracellular matrix enhances angiogenesis, a process crucial for blood vessel growth. This study reveals proline-rich tyrosine kinase 2 (Pyk2) plays a key role in this adhesive regulation.
Area of Science:
- Cell Biology
- Biochemistry
- Developmental Biology
Background:
- Angiogenesis, the formation of new blood vessels, is critical for development and disease.
- It is regulated by growth factors and cell interactions with the extracellular matrix (ECM).
- The precise role of quantitative changes in cell adhesion to the ECM in angiogenesis is not fully understood.
Purpose of the Study:
- To investigate the impact of varying cell adhesion levels to the ECM on angiogenic sprouting.
- To identify the underlying genetic and molecular mechanisms governing this response.
- To elucidate the role of focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) in adhesion-regulated angiogenesis.
Main Methods:
- Quantitative assessment of angiogenic sprouting in 3D matrices with controlled adhesion.
- Global gene expression analysis to identify molecular pathways involved.
- Investigation of FAK and Pyk2 signaling pathways.
- Analysis of angiogenic sprouting in Pyk2-null mouse tissue explants.
Main Results:
- Angiogenesis exhibited a biphasic response to matrix adhesion, peaking at intermediate levels.
- Limited cell adhesion promoted vascular invasion and remodeling gene expression, while high adhesion favored proliferation genes, both in response to vascular endothelial growth factor (VEGF).
- Pyk2, activated by VEGF under limited adhesion, regulated gene expression and endothelial sprouting, confirmed by experiments with Pyk2-null mice.
Conclusions:
- Intermediate cell adhesion to the ECM optimizes angiogenic sprouting.
- Limited adhesion enhances endothelial cell responsiveness to VEGF, influencing gene expression.
- Pyk2 is a novel regulator of angiogenesis, mediating the effects of cell adhesion on endothelial sprouting and gene expression.
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