The Atherosusceptible Endothelium: Endothelial Phenotypes in Complex Haemodynamic Shear Stress Regions in vivo.

Davies PF, Civelek M, Fang Y, Fleming I. Cardiovasc Res. 2013 Jul 15

Abstract

Atherosclerosis initiates at predictable focal sites and develops to a spatially regional disease with limited distribution. There is compelling evidence that links haemodynamics to the localized origin of atherosclerotic lesions. Arterial flow in vivo is unsteady, dynamically complex, and regionally variable. Sites susceptible to atherosclerosis near arterial branches and curves are associated with regions of disturbed blood flow that contain repetitive phases of flow reversal resulting in steep multidirectional temporal and spatial gradients of wall shear stresses. Endothelium in atherosusceptible regions relative to protected sites shows activation of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), the altered expression of pro-inflammatory Nuclear Factor kappa B (NFκB) and oxidant/antioxidant pathways, and low expression of major protective factors, notably endothelial nitric oxide synthase and Kruppel-like Factors KLF2 and KLF4. At some atherosusceptible locations, reactive oxygen species levels are significantly elevated. Here we describe flow-related phenotypes identified in steady-state in vivo and outline some of the molecular mechanisms that may contribute to pre-lesional atherosusceptibility as deduced from complementary cell experiments in vitro. We conclude that disturbed flow is a significant local risk factor for atherosclerosis that induces a chronic low-level inflammatory state, an adaptive response to ensure continued function at the expense of increased susceptibility to atherogenesis. Surprisingly, when challenged by short-term hypercholesterolaemia in vivo, atherosusceptible endothelial phenotype was resistant to greater pro-inflammatory expression, suggesting that sustained hyperlipidaemia is required to overcome these protective characteristics.

A schema of regulatory mechanisms of endothelial atherosusceptibility discussed in the text. Flow disturbance in regions susceptible to atherogenesis places a stress load on the biosynthetic capacity of the endothelial endoplasmic reticulum (ER) that leads to ER stress. Activation of the unfolded protein response (UPR) compensates to maintain normal cell function but a residual low-level chronic inflammatory state persists. Pro-inflammatory molecules are up-regulated (left) and protective molecules down-regulated (right). MicroRNAs (miRs) regulated up or down by disturbed flow regulate (at least in part) the pro-inflammatory state and are shown in a reciprocal transcriptional relationship to their targets. Notes: eNOS is a direct target of miR-155, inhibiting eNOS in cytokine-induced inflammation, however, differential miR-155 expression has not yet been demonstrated in disturbed flow. miR-143/145 is increased by flow-induced suppression of KLF2 and is shed in endothelial exosomes (Figure 5D). Not shown in this schema or discussed in the text (because of space limitations) are other regulatory mechanisms believed to contribute to endothelial pro-inflammatory phenotype through the MAPK pathway that mimics cytokine-induced mechanisms and through a low level of protective Nrf2 in atherosusceptible endothelium in mice.17

A schema of regulatory mechanisms of endothelial atherosusceptibility discussed in the text. Flow disturbance in regions susceptible to atherogenesis places a stress load on the biosynthetic capacity of the endothelial endoplasmic reticulum (ER) that leads to ER stress. Activation of the unfolded protein response (UPR) compensates to maintain normal cell function but a residual low-level chronic inflammatory state persists. Pro-inflammatory molecules are up-regulated (left) and protective molecules down-regulated (right). MicroRNAs (miRs) regulated up or down by disturbed flow regulate (at least in part) the pro-inflammatory state and are shown in a reciprocal transcriptional relationship to their targets. Notes: eNOS is a direct target of miR-155, inhibiting eNOS in cytokine-induced inflammation, however, differential miR-155 expression has not yet been demonstrated in disturbed flow. miR-143/145 is increased by flow-induced suppression of KLF2 and is shed in endothelial exosomes (Figure 5D). Not shown in this schema or discussed in the text (because of space limitations) are other regulatory mechanisms believed to contribute to endothelial pro-inflammatory phenotype through the MAPK pathway that mimics cytokine-induced mechanisms and through a low level of protective Nrf2 in atherosusceptible endothelium in mice.

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