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Angiogenesis: Just add sugar

Functional Glycomics (11 February 2010) | doi:10.1038/fg.2010.8

Decoration of an endothelial cell surface molecule with sialic acids is necessary to support the maintenance of new blood vessels.

Image courtesy of Mary O’Reilly

Healing wounds and developing embryos require extra oxygen and nutrients to support new cell growth. To this end, cells release growth factors and other cues to stimulate angiogenesis, the formation of new blood vessels. However, metastatic tumors can also exploit angiogenesis to divert blood supply and ensure survival far from their point of origin. Angiogenesis is regulated in part by the platelet endothelial cell adhesion molecule (PECAM), a surface glycoprotein that helps control the activation and survival of endothelial cells. Writing in the Journal of Biological Chemistry, Naoyuki Taniguchi and colleagues reveal that modification with one particular sugar, α2,6-sialic acid, is required for PECAM localization and function.

The authors first noticed that PECAM expression was changed in knockout mice lacking ST6Gal I, the enzyme that adds α2,6-sialic acid to glycoproteins. Normally, PECAM is readily detected on the cell surface. Yet in endothelial cells obtained from ST6Gal I-deficient mice, most PECAM molecules were internalized and very few were found on the cell surface. Overexpression of ST6Gal I in these cells was enough to restore PECAM to its normal location. The authors concluded that decoration with α2,6-sialic acid is necessary to maintain PECAM on endothelial cell surfaces.

To help build a blood vessel, PECAM molecules on the surface of one endothelial cell interact with PECAM molecules on other cells. Pull-down assays revealed that α2,6-sialic acid-deficient PECAM does not bind other PECAM molecules. Lack of ST6gal I expression in endothelial cells also hampered the PECAM-mediated cell signaling and increased endothelial cell sensitivity to stimuli that trigger apoptosis. These results suggest that proper PECAM localization, mediated by α2,6-sialic acid, is essential for its role in angiogenesis.

Sialic acid-mediated disruption of PECAM localization and function presumably disrupts angiogenesis, making it harder for tumors to survive. Based on this new understanding of the role sialylation plays in angiogenesis, the authors speculate that cells might use sialylation as a mechanism for regulating angiogenesis in various normal and pathological states. Moreover, these findings imply that tweaking sugar expression could provide a new avenue for the development of anti-angiogenesis therapies for metastatic cancer.

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Original research paper

  1. Kitazume, S. et al. α2,6-Sialic acid on platelet endothelial cell adhesion molecule (PECAM) regulates its homophilic interactions and downstream antiapoptotic signaling. J. Biol. Chem. (Published online 5 January 2010) doi:10.1074/jbc.M109.073106 | Article |