Haemodynamic Wall Shear Stress, Endothelial Permeability and Atherosclerosis-A Triad of Controversy.

Peter D Weinberg

doi:10.3389/fbioe.2022.836680

Abstract

A striking feature of atherosclerosis is its patchy distribution within the vascular system; certain arteries and certain locations within each artery are preferentially affected. Identifying the local risk factors underlying this phenomenon may lead to new therapeutic strategies. The large variation in lesion prevalence in areas of curvature and branching has motivated a search for haemodynamic triggers, particular those related to wall shear stress (WSS). The fact that lesions are rich in blood-derived lipids has motivated studies of local endothelial permeability. However, the location of lesions, the underlying haemodynamic triggers, the role of permeability, the routes by which lipids cross the endothelium, and the mechanisms by which WSS affects permeability have all been areas of controversy. This review presents evidence for and against the current consensus that lesions are triggered by low and/or oscillatory WSS and that this type of shear profile leads to elevated entry of low density lipoprotein (LDL) into the wall via widened intercellular junctions; it also evaluates more recent evidence that lesion location changes with age, that multidirectional shear stress plays a key role, that LDL dominantly crosses the endothelium by transcytosis, and that the link between flow and permeability results from hitherto unrecognised shear-sensitive mediators.

Highlights

A striking feature of atherosclerosis is its non-uniform distribution within the arterial system
There is no need to postulate that disease is triggered by variation in intimal macromolecule accumulation that has an undetected anatomical distribution opposite to that seen in the wall as a whole
When uptake of albumin measured over the entire intima-media is higher downstream of branches than upstream, the same is true for uptake in the innermost layers of the wall; there is no indication of a reversed pattern in the innermost layers that could account for an upstream distribution of lesions (Sebkhi and Weinberg, 1996)

Summary

INTRODUCTION

A striking feature of atherosclerosis is its non-uniform distribution within the arterial system. A small study (Sebkhi and Weinberg, 1994b) of quasi-steady albumin uptake showed that feeding mature rabbits 0.2% cholesterol for 1 week reversed the usual pattern of transport, so that uptake became greater downstream than upstream of intercostal branch ostia, as in immature animals. A subsequent trial (Cremers et al, 2011) in which immature and mature rabbits of the second strain were given the same diet for the same length of time unequivocally gave the arrowhead pattern at intercostal branch ostia of the immature animals and a more lateral pattern in the mature ones (Figure 3C) To confirm that this unexpected effect of strain applies to the pattern of transport as well as lesions, short-term uptake of albumin was examined in two strains of rabbit (Staughton and Weinberg, 2004a). It is interesting to speculate that, as with rabbits, different populations may undergo the swich at different ages

Conclusion

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CONCLUSION