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This Article Full Text Full Text (PDF) Supplemental Videos All Versions of this Article: 297/1/C179    most recent 00018.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kniazeva, E. Articles by Putnam, A. J. PubMed PubMed Citation Articles by Kniazeva, E. Articles by Putnam, A. J.

EXTRACELLULAR MATRIX, CELL INTERACTIONS

Endothelial cell traction and ECM density influence both capillary morphogenesis and maintenance in 3-D

¹Department of Biomedical Engineering and ²Department of Chemical Engineering and Materials Sciences, University of California, Irvine, Irvine, California

Submitted 13 January 2009 ; accepted in final form 11 May 2009

Identifying the mechanisms regulating angiogenesis in pathological conditions such as cancer and heart disease is crucial to develop successful therapies. The dependence of angiogenesis on characteristic properties of these conditions, such as alterations in tissue stiffness due to changes in the composition of the extracellular matrix (ECM), may shed light on potential therapeutic strategies. Prior studies have suggested that ECM compliance regulates capillary morphogenesis, but the mechanisms remain unclear. In this study, we hypothesized that ECM density, which influences substrate mechanics, may regulate angiogenesis via a mechanism involving actin-mediated cell-generated forces. To investigate this hypothesis, we utilized an in vitro model of angiogenesis in which endothelial cells coated on microcarrier beads are distributed within a three-dimensional (3-D) fibrin ECM. A monolayer of fibroblasts, which provides pro-angiogenic factors, is cultured on top of the gel. Variations in fibrin gel density, along with a library of pharmacological agents that inhibit forces generated by the actin cytoskeleton, were used to prove the necessity of cell-generated tractional forces in blood vessel formation. Our data demonstrate that cell-generated forces not only play a crucial role in the early sprouting stages of capillary morphogenesis but are also required in the later maintenance stages, and thereby suggest a broader interdependence among tissue stiffness, cell contractile forces, and angiogenesis.

angiogenesis; traction forces; actin; extracellular matrix stiffness