Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity - The Mechanobiology of Obesity and Related Diseases - page 213

activated neutrophils circulating in the bloodstream or adhered in the microcircu-
lation release vasoactive substances that either constrict the small arteries and
arterioles or promote a systemic inflammatory scenario that influences endothelial
dysfunction [ 7 , 10 ].
It, however, is also possible that hypertension-related microvascular dysfunc-
tion arises from a hemorheological effect of leukocyte activation on microvascular
resistance [ 7 , 86 , 90 ]. Specifically, the disturbed motion of white blood cells due to
pseudopod projection has been shown to significantly reduce erythrocyte velocities
in the capillaries and/or disrupt the organized motion of RBCs in the non-capillary
microcirculation, with an effect on hemodynamic resistance and upstream blood
pressures (Fig. 3 ).
Evidence for the possibility that impaired neutrophil mechanosensitivity may
contribute to obesity-related microvascular dysfunction is found within rats
exhibiting a chronically inflamed phenotype due to spontaneous hypertension.
These rats exhibit pathological elevations in hemodynamic resistance due to the
elevated numbers of neutrophils that lack a pseudopod retraction response to shear
[ 12 ]. Interestingly, neutrophils in the blood of hypertensive rats, while exhibiting
an activated phenotype, also display reduced expression of cell-cell adhesion
molecules. These further suggest that the pseudopod retraction responses of neu-
trophils to shear stress contribute, at least in part, to the reported elevations in
microvascular resistance associated with hypertension.
Notably, the underlying mechanism associated with the blockade and possible
reversal of the pseudopod retraction response to shear stress reportedly involves
the dependence of blood pressure in spontaneously hypertensive rats on the plasma
level of glucocorticoid-related steroid hormones and the density of glucocorticoid
receptors on the neutrophil surface [ 140 , 141 ]. Glucocorticoids also block the
neutrophil pseudopod retraction response to shear stress [ 140 ]. In this fashion, the
link between an impaired neutrophil pseudopod retraction response to shear and
hemodynamic resistance in rats was confirmed using glucocorticoid-treated rats
[ 140 ]. As a result, elevated peripheral resistance due to a chronic inflammatory
state has been attributed to an impaired neutrophil shear response promoting
capillary plugging or adhesion to venular endothelium.
Hypercholesterolemia is also a potential contributor of dysregulated neutrophil
activity due to obesity [ 142 ]. Notably, we recently reported [ 9 ] that shear-induced
pseudopod retraction by neutrophils depends (R 2 = 0.9; p\0.01) on the choles-
terol-related fluidity of the cell membrane. Moreover, the neutrophil pseudopod
retraction response to shear is impaired in a time-dependent fashion during the
onset and progression of hypercholesterolemia [ 9 ] with a putative downstream
impact on tissue blood flow autoregulation [ 8 ].
Furthermore, based on the role of CD11b/CD18 in neutrophil adhesion, our
findings [ 104 - 106 ] also suggest that shear-induced CD11b/CD18 shedding averts
cell adhesion during non-inflamed states. In contrast, a loss of the ability of shear
stress to minimize neutrophil adhesion in microvessels may be another down-
stream impact of blood cholesterol elevations on microvascular resistance.