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Endothelial growth factors and extracellular matrix regulate DNA synthesis through modulation of cell and nuclear expansion

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EDITOR'S STATEMENT This manuscript describes the important relationship between growth factors and extracellular matrix components and nuclear and cytoplasmic structure. It further demonstrates that matrix molecules may play a regulatory role in angiogenesis by preventing endothelial cells from undergoing cytostructural reorganization in response to growth factors. Mina J. Bissell

Summary

Studies were carried out to analyze the mechanism by which extracellular matrix (ECM) molecules and soluble growth factors interplay to control capillary endothelial cell growth. Bovine adrenal capillary endothelial cells attached to purified matrix components but spread poorly and exhibited low levels of DNA synthesis in the absence of exogenous growth factors or serum. Addition of cationic, heparin-binding growth factor purified from either human hepatoma cells or normal bovine pituitary (fibroblast growth factor) induced extensive cell spreading and up to eight fold increases in DNA synthetic rates relative to levels observed in cells on similar substrata in the absence of mitogen. However, the extent of this response differed depending upon the type of ECM molecule used for cell attachment (fold increase on type III collagen > gelatin > type IV collagen > fibronectin > type V collagen ⋙ laminin). Computerized morphometry demonstrated that endothelial cell DNA synthetic rates increased in an exponential fashion in direct relation to linear increases in cell and nuclear size (projected areas). Similarly sized cells always displayed the same level of DNA synthesis independent of the type of ECM molecule used for cell attachment or the presence of saturating amounts of growth factor. In all cases, DNA metabolism appeared to be coupled to physical expansion of the cell and nucleus rather than to a specific cell morphology (e.g. polygonal versus bipolar). These findings suggest that ECM may act locally as a “solid state” regulator of angiogenesis through its ability to selectively support or prohibit cell and nuclear extension in response to stimulation by soluble mitogens.

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Author information

Authors and Affiliations

  1. Department of Surgery, The Children's Hospital, Department of Pathology, Brigham and Women's Hospital, 02115, Boston, Massachusettes

    Donald E. Ingber

  2. Department of Anatomy and Cell Biology, Harvard Medical School, 02115, Boston, Massachusettes

    Judah Folkman

  3. Department of Pathology, Yale University School of Medicine, 06510, New Haven, Connecticut

    Joseph A. Madri

Authors
  1. Donald E. Ingber
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  2. Joseph A. Madri
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  3. Judah Folkman
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Additional information

This work was supported by an Anna Fuller Fund postdoctoral fellowship (D.E.I.), USPHS grants HL-28373 (J.A.M.) and CA-37395 (J.F.), and a grant from the Monsanto Company to Harvard University.

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Ingber, D.E., Madri, J.A. & Folkman, J. Endothelial growth factors and extracellular matrix regulate DNA synthesis through modulation of cell and nuclear expansion. In Vitro Cell Dev Biol 23, 387–394 (1987). https://doi.org/10.1007/BF02620997

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