Endothelial Dysfunction, Hemodynamic Forces, and Atherogenesis^a

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.

Neutrophil Adhesion on Endothelial Cells in a Novel Asymmetric Stenosis Model: Effect of Wall Shear Stress Gradients

“…Hinds et al found a similar increased adhesion of U-937 cells to the proximal part of the constriction in their idealized E-selectin coated axisymmetric stenosis (49). Taken together, our results and previous studies suggest that there is more firm attachment of leukocytes to an endothelium in the presence of complex shear gradients (31)(32)(33).…”

“…Most of our understanding of leukocyte adhesion and endothelial cell dysfunction has come from parallel plate and rotational viscometer cell culture experiments (31,32). These studies have demonstrated that leukocyte attachment is dependent on the magnitude of the hydrodynamic forces, the contact frequency and duration, and the cellular response to shear stress (29,(33)(34)(35)(36).…”

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

“…Indications that mechanical stimulation of cells, and endothelium in particular, is able to change some of their functions at biochemical and molecular level are reported in the literature [5]. In spite of the evidence that cells are sensitive to mechanical stimuli, the molecular mechanisms by which individual cells recognize and respond to external forces are not well understood.…”

“…Endothelial cells are the true player of the angiogenesis process. Several cardiovascular pathologies are caused by endothelial dysfunction (myocardial ischemia, atherosclerosis), thus growth factors and strategies able to restore the integrity of the endothelium and to promote angiogenesis can be viewed as innovative therapeutic approaches [3,4].Indications that mechanical stimulation of cells, and endothelium in particular, is able to change some of their functions at biochemical and molecular level are reported in the literature [5]. In spite of the evidence that cells are sensitive to mechanical stimuli, the molecular mechanisms by which individual cells recognize and respond to external forces are not well understood.…”

El Consumo De Frutas Y Hortalizas Ayuda a Prevenir El Daño Endotelial

“…Una característica común de la disfunción endotelial es la disminución de la biodisponibilidad de NO a nivel vascular (56), acompañada de otras alteraciones en el fenotipo endotelial que aumentan aún más la propensión a la vasoconstricción (57), trombosis, inflamación y a la proliferación celular en el lecho vascular (58)(59)(60)(61). La disfunción endotelial es el resultado de la presencia de FRCV y el desarrollo de aterosclerosis (62).…”