Endothelial Heterogeneity Associated with Regional Athero-Susceptibility and Adaptation to Disturbed Blood Flow in Vivo

Abstract

Endothelial phenotypic heterogeneity plays an important role in the susceptibility of the cardiovascular system to disease. Arteries and heart valves are susceptible to chronic inflammatory disease in regions of blood flow disturbance that implicates hemodynamic forces and transport characteristics as prominent influences on endothelial phenotype. By combining in vivo high-throughput genomics (discovery science) and in vitro mechanistic approaches (reductionist science), we present endothelial patho-susceptibility as an imbalance of multiple interrelated pathways that sensitize the cells to pathological change. The recently identified association of endoplasmic reticulum stress with endothelium in regions of flow disturbance is outlined as an important example of susceptible phenotype linked to proinflammatory and oxidative stress pathways.

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

“…The aortic endothelium derived from representative sites of susceptibility, and resistance to atherosclerosis studied in swine revealed regional heterogeneity consistent with priming for inflammation and sensitization to pathological change at sites of flow disturbance (8,15,32). The emerging paradigm is that disturbed flow is permissive to atherosclerosis in that it contributes to a state of chronic stress that might be exacerbated by factors that affect systemic inflammation, causing a transition of the endothelium to a state of dysfunction that precedes pathology (12). Consistent with this view of vulnerable endothelium, our data demonstrate that IRF-1 is more highly expressed at sites of atherosusceptibility in the arteries of disease-free swine.…”

“…However, while shear stress has been established as a determinant of the endothelial inflammatory phenotype, its influence alone is not sufficient to induce pathological changes in the endothelium. Rather, it is believed to contribute to an unsteady state of equilibrium in endothelial function, which can be tipped toward atherogenesis in the presence of risk factors that contribute to systemic inflammation (12).…”

Cooperation of Nature and Physiologically Inspired Mechanisms in Visualisation

“…In regions with unstable flow such as curvatures, branches and bifurcations in the arterial circulation, steep temporal and spatial gradients of shear stress are associated with an oscillatory flow that act on the endothelial cells. In these regions of disturbed oscillatory flow, multidirectional forces act on the cells, and as a result, the endothelium, unlike elsewhere in the arterial circulation, lacks preferential cell alignment and often expresses a polygonal morphology (Davies et al, 2010). Disturbed flow regions correlate closely with susceptibility to pathological change such as atherosclerosis in arteries and calcific sclerosis in heart valves.…”

Endothelial and Vascular Smooth Cell Dysfunctions: A Comprehensive Appraisal

“…ECs dysfunction has been shown to be associated with an increase of ROS in atherosclerotic animal models and in human subjects with atherosclerosis (Dai, D.Z. & Dai, Y., 2010;Davies et al, 2010;Higashi et al, 2009). Moreover, in APOE-deficient mice, a widely used animal model of atherosclerosis (Xu, 2009;Zhang, S.H.…”

“…NF-kB is normally held inactive in the cytosol as a complex with IkB, a family of inhibitors of NFkB. Oxidative stress by ROS production induces IkB degradation, releases of NFkB for translocation to the nucleus where it regulates pro-inflammatory genes (Davies et al, 2010). Several pro-inflammatory cytokines and growth factors found in atherosclerotic lesions, such as TNF , ILs, MCP-1 and tissue factors, activate NF-kB signaling pathway in cultured ECs (Pennathur & Heinecke, 2007).…”