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Endothelial Dysfunction, Hemodynamic Forces, and Atherogenesisa

Authors

  • MICHAEL A. GIMBRONE JR.,

    Corresponding author
    1. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115–5817, USA
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  • JAMES N. TOPPER,

    1. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115–5817, USA
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    • c

      Current address: Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Drive, Stanford CA 94305.

  • TOBI NAGEL,

    1. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115–5817, USA
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    • d

      Current address: Genentech, 1 DNA Way, MS 34, So. San Francisco, CA 94080–4990.

  • KEITH R. ANDERSON,

    1. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115–5817, USA
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  • GUILLERMO GARCIA-CARDEÑA

    1. Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115–5817, USA
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  • a

    This research was supported primarily by grants from the National Heart, Lung and Blood Institute (P01-HL36028, R37-HL51150, P50-HL56985) and a sponsored research agreement with the Brigham and Women's Hospital from Millennium Pharmaceuticals, Inc. (Cambridge, MA).

Address for correspondence: Michael A. Gimbrone, Jr., Vascular Research Division, Department of Pathology, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115. Voice: 617–732–5901; fax: 617–732–5933. mgimbrone@rics.bwh.harvard.edu

Abstract

Abstract: Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NFκB and Egr-1, to shear-stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up- and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non-laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL-1β). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX-2, and Mn-SOD) support vasoprotective (i.e., anti-inflammatory, anti-thrombotic, anti-oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related “atheroprotective genes” in the endothelial lining of lesion-protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.

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