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. 2005 Feb 1;562(Pt 3):647-53.
doi: 10.1113/jphysiol.2004.079640. Epub 2004 Dec 20.

The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia?

Karen Y Stokes  1 , D Neil Granger
Affiliations

The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia?

Karen Y Stokes et al. J Physiol. .

Abstract

There is abundant evidence that links hypercholesterolaemia to both vascular inflammation and atherogenesis. While atherosclerosis is a large vessel disease that is characterized by leucocyte infiltration and lipid deposition in the wall of lesion-prone arteries, the inflammatory response does not appear to be confined to these locations. There is evidence supporting a systemic inflammatory response that is characterized by endothelial cell activation in multiple vascular beds and the appearance of activated immune cells and a wide range of inflammatory mediators in blood. The mechanism(s) responsible for initiating this systemic response remain poorly defined, although several inciting factors have been proposed, including infectious agents and oxidative stress resulting from one or more of the cardiovascular risk factors (e.g. hypercholesterolaemia, hypertension). While cells within lesion-prone arteries are often inferred as the source of circulating inflammatory mediators during atherogenesis, the fact that endothelial cells throughout the vasculature are activated raises the possibility that the microvasculature (which encompasses a vast endothelial surface area) may contribute to creating the systemic inflammatory milieu that is linked to atherogenesis. This review addresses evidence that links the microvasculature to the inflammatory responses induced by hypercholesterolaemia and offers the hypothesis that inflammatory events initiated within the microcirculation may contribute to initiation and/or progression of large vessel disease.

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Figures

Figure 1
Figure 1. Mechanism proposed to link early inflammatory events initiated in the microvasculature to the large vessel disease induced by hypercholesterolaemia
Arterioles experience an oxidative stress characterized by reduced nitric oxide (NO) bioavailability, elevated superoxide (O2−) generation and decreased vasorelaxation. This leads to attenuated tissue perfusion. Venules also respond to hypercholesterolaemia with oxidative stress, which promotes adhesive interactions between (and the activation or priming of) circulating neutrophils, platelets and venular endothelial cells. Cytokines derived from other activated leucocytes (e.g. IFN-γ from T-lymphocytes) contribute to the enhanced superoxide production in venules. The resultant appearance of inflammatory mediators and activated blood cells in venous blood and the systemic circulation may act in concert with the flow disturbances and other physical factors that are unique to lesion-prone arteries to initiate the development of an atherosclerotic plaque. The plaque shares many inflammatory characteristics with the microvasculature, including oxidative stress, increased adhesion molecule expression, leucocyte and platelet recruitment, and cytokine release.
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