Endothelial dysfunction, hemodynamic forces, and atherogenesis.
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.
Gimbrone
M A
MA
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115-5817, USA. mgimbrone@rics.bwh.harvard.edu
Topper
J N
JN
Nagel
T
T
Anderson
K R
KR
Garcia-Cardeña
G
G
D000818:Animals; D001158:Arteries / Q000503:physiopathology*; D001161:Arteriosclerosis / Q000235:genetics / Q000503:physiopathology*; D001696:Biomechanical Phenomena; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005786:Gene Expression Regulation; D006439:Hemodynamics; D006801:Humans; D013314:Stress, Mechanical