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Endothelial dysfunction, hemodynamic forces, and atherogenesis
M A Gimbrone1, J N Topper, T Nagel
1Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115-5817, USA. mgimbrone@rics.bwh.harvard.edu
Insights
Hemodynamic forces influence atherosclerosis by regulating endothelial genes. Specific shear stresses activate protective genes, potentially preventing lesion formation in arteries.
Area of Science:
- Cardiovascular Biology
- Translational Medicine
- Biophysics
Background:
- Endothelial dysfunction contributes to atherosclerosis pathogenesis.
- Atherosclerotic lesions often localize to areas with disturbed blood flow patterns.
- The vascular endothelium senses and responds to hemodynamic forces from pulsatile blood flow.
Purpose of the Study:
- To investigate how hemodynamic forces regulate endothelial gene expression.
- To explore the role of specific shear stress patterns in atherogenesis.
- To identify endothelial genes involved in atheroprotection.
Main Methods:
- Analysis of gene regulation by transcription factors (NF kappa B, Egr-1) and shear-stress response elements (SSREs).
- Comparison of gene expression patterns under steady laminar versus non-laminar shear stress.
- Examination of endothelial response to cytokine stimulation (e.g., IL-1 beta).
Main Results:
- Steady laminar shear stress upregulates atheroprotective genes like eNOS, COX-2, and Mn-SOD.
- Distinct gene expression patterns are induced by different shear stress types and cytokine stimulation.
- Transcription factors bind to SSREs in biomechanically inducible genes.
Conclusions:
- Hemodynamic forces selectively regulate endothelial gene expression.
- Upregulation of atheroprotective genes by laminar shear stress may prevent lesion formation.
- Endothelial response to mechanical forces is a key factor in atherosclerosis development.
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 NF kappa B 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-1 beta). 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.