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ATHEROSCLEROSIS

Transforming endothelial cells in atherosclerosis

Nature Metabolism volume 1, pages 856–857 (2019)Cite this article

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Cells contributing to atherosclerotic disease are highly plastic and can shift their phenotype in a changing microenvironment. A study in Nature Metabolism now reveals that transforming growth factor-β (TGF-β) can transform endothelial cells into pro-inflammatory cells and that inhibition of TGF-β-receptor signalling in the endothelium can reverse atherosclerosis in mice.

Endothelial cells (ECs) line all blood vessels and are critical mediators of inflammatory responses. In the setting of atherosclerosis, ECs become chronically activated through a combination of turbulent blood flow, lipid accumulation in the vessel wall and exposure to inflammatory mediators (for example, IL-1β)1. The activated endothelium in turn orchestrates the recruitment and maintenance of inflammatory cells in the expanding atherosclerotic plaque. Understanding how ECs respond to the complex inflammatory microenvironment driving plaque initiation, progression and maintenance is requisite for effective therapy. Recent clinical trials have revealed that globally antagonizing IL-1β signalling significantly (though modestly) decreases cardiovascular events in patients with elevated systemic inflammation despite effective lipid control2, thus providing proof-of-concept evidence that targeting inflammation may be a feasible approach to combat atherosclerosis. However, IL-1β antagonism is also associated with an elevated risk of fatal infections2. Targeted therapy is clearly warranted. The response of the endothelium to inflammatory stimuli has been identified as one such target. Beyond expressing leukocyte adhesion molecules and producing chemokines that communicate to circulating and resident inflammatory cells, activated ECs can transform into mesenchymal-like cells in a process known as endothelial-to-mesenchymal transition (EndMT). These cells either co-express EC and mesenchymal markers (a state referred to as partial EndMT) or fully lose EC identity, delaminate from the endothelium and contribute to populations of fibroblasts and, to a lesser extent, smooth muscle cells in the plaque interior3,4. Because EndMT has been linked to vulnerable atherosclerotic plaques and clinical events4, understanding how this process is regulated could lead to the development of effective therapeutic approaches.

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Fig. 1: Endothelial TGF-β signalling drives atherogenesis.

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Authors and Affiliations

  1. Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada

    Kathryn L. Howe & Jason E. Fish

  2. Division of Vascular Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    Kathryn L. Howe

  3. Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada

    Kathryn L. Howe & Jason E. Fish

  4. Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Jason E. Fish

Authors
  1. Kathryn L. Howe
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  2. Jason E. Fish
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Correspondence to Kathryn L. Howe or Jason E. Fish.

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The authors declare no competing interests.

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Howe, K.L., Fish, J.E. Transforming endothelial cells in atherosclerosis. Nat Metab 1, 856–857 (2019). https://doi.org/10.1038/s42255-019-0100-5

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