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Atherogenesis: Estrogen Induction of Polysialylated nCAM (PSA-nCAM) Blocks Monocyte Capture by Vascular Endothelial Cells

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Sex Steroids' Effects on Brain, Heart and Vessels

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Abstract

Atherosclerosis begins with the formation of subendothelial vascular atheromas. Atheroma formation requires the capture of monocytes by the vessel wall endothelial cells. To arrest passing leukocytes, the vascular endothelium deploys cell surface neural cell molecule (nCAM) to form polymers (tethers) with nCAM on the surface of passing monocytes. The arrested monocytes are then bound by cadherins, adhere to the endothelial surface, and migrate into the subendothelial stroma. They then undergo transformation to foam cells and are incorporated in atheroma plaque. The formation of nCAM polymers is dependent on electrostatic binding of extracellular domains of nCAM molecules. We consider the capture of monocytes to be a nexus in atherogenesis, in which the monocytes that are required to form plaque are furnished to the plaque-forming milieu of the vessels: no monocytes, no plaque. Sialylation of nCAM renders it unable to form nCAM polymers, breaking the chain at this vulnerable nexus between circulating leukocytes and endothelial binding/penetration.

Estrogen is anti-atherogenic. We showed that estradiol induces the expression of nCAM sialylases in vascular endothelium and proposed that estrogen-induced sialylation of nCAM inhibits the capture of leukocytes from the blood. To test this hypothesis, we employed in vitro culture of cardiovascular endothelial cells from women’s and men’s coronary vessels. Hormone-treated monolayers of endothelial cells were seeded with green fluorescence-labeled human monocytes; after suitable incubation the free monocytes were washed away, and the number of monocytes captured by sex steroid-treated endothelial cells vs. untreated cells was assessed. Significantly fewer monocytes were captured by estradiol-pretreated human endothelial cells than by control vehicle controls. The estradiol effect was blocked by co-pretreatment with an antagonist SERM. We obtained similar results regarding nCAM sialylation and monocyte capture with other sex steroids: testosterone, dihydrotestosterone, and dehydroepiandrosterone (DHEA). Preliminary studies indicate that this was related to interaction of these steroids or their metabolites with estrogen receptors, which may explain their estrogen-like action. This is presently under study.

We conclude that one of the anti-atherogenic actions of estrogen is to induce the polysialylation of nCAM, inhibiting tethering of intravascular monocytes to the vascular endothelium. This could interfere with a key nexus for the beginning of atherogenesis and atherosclerosis.

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Acknowledgments

Support—NIH HL100769. Helpful conversations with Drs. Gil Mor and Andrei Kindzelski are gratefully acknowledged.

Support NIH HL 796100

Conflicts: None

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, New York University, New York, NY, USA

    Frederick Naftolin

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  1. Frederick Naftolin
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Correspondence to Frederick Naftolin .

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Editors and Affiliations

  1. Center for Innovation in Brain Sciencies-Department of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA

    Roberta Diaz Brinton

  2. International School for Gynecological and Reproductive Endocrinology, International Society of Gynecological Endocrinology, Locarno, Switzerland

    Andrea R. Genazzani

  3. Department of Clinical and Experimental Medicine, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy

    Tommaso Simoncini

  4. National Heart and Lung Institute, Imperial College London, London, UK

    John C. Stevenson

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© 2019 International Society of Gynecological Endocrinology

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Naftolin, F. (2019). Atherogenesis: Estrogen Induction of Polysialylated nCAM (PSA-nCAM) Blocks Monocyte Capture by Vascular Endothelial Cells. In: Brinton, R., Genazzani, A., Simoncini, T., Stevenson, J. (eds) Sex Steroids' Effects on Brain, Heart and Vessels. ISGE Series. Springer, Cham. https://doi.org/10.1007/978-3-030-11355-1_15

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  • DOI: https://doi.org/10.1007/978-3-030-11355-1_15

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-11354-4

  • Online ISBN: 978-3-030-11355-1

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