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Review
. 2013 Jan-Feb;22(1):9-15.
doi: 10.1016/j.carpath.2012.06.006. Epub 2012 Jul 18.

Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis

Michael A Gimbrone Jr  1 , Guillermo García-Cardeña
Affiliations
Review

Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis

Michael A Gimbrone Jr et al. Cardiovasc Pathol. 2013 Jan-Feb.

Abstract

The localization of atherosclerotic lesion formation to regions of disturbed blood flow associated with certain arterial geometries, in humans and experimental animals, suggests an important role for hemodynamic forces in the pathobiology of atherosclerosis. 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 different biomechanical stimuli and transduce them into genetic regulatory programs that modulate endothelial function. In this brief review, we discuss how biomechanical stimuli generated by blood flow can influence endothelial functional phenotypes, and explore the working hypothesis of "atheroprone" hemodynamic environments as "local risk factors" in atherogenesis. In addition, we consider the therapeutic implications of the activation of "atheroprotective genes" and their role as "critical regulatory nodes" in vascular homeostasis.

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Figures

Fig. 1
Fig. 1
Nonrandom pattern of early atherosclerotic lesion development in mouse aorta. (A) Dissected aortic arch from a LDL receptor-deficient (LDLR−/−) mouse fed a cholesterol-rich diet stained with oil red-O to mark early atherosclerotic lesions (adapted from Ref. [65]). (B) Location of “atherosclerosis-resistant” and “atherosclerosis-susceptible” regions, indicated on an intact mouse aorta, corresponding to the descending thoracic aorta and the lesser curvature of the aortic arch, respectively. (C) En face confocal microscopy of the endothelium of these regions showing distinct cell shapes (cell junctions stained for CD31).
Fig. 2
Fig. 2
A novel in vitro biomechanical model system for the analysis of atheroprotective and atheroprone endothelial phenotypes in human endothelial cells. Computational fluid mechanical analysis of flow patterns of the normal human carotid artery yielded two prototypic arterial waveforms–“atheroprotective” and “atheroprone,” representative of the wall shear stresses of the carotid sinus and the distal internal carotid artery, which are typically “susceptible” or “resistant,” respectively, to atherosclerosis. These biomechanical stimuli were recreated on the surface of cultured human endothelial monolayers in a dynamic flow system, and the resultant transcriptomes were subjected to detailed bioinformatic analyses.
Fig. 3
Fig. 3
Critical regulatory nodes in vascular homeostasis. Induction of the transcription factors KLF2 and Nrf2 by atheroprotective flow orchestrates a multifunctional genetic program, the net effects of which contribute to the maintenance of endothelial vasoprotective phenotypes. Statins, and potentially other yet-to-be-defined agents, through their induction of KLF2 can function as pharmacomimetics of atheroprotective flow.
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