Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity - The Mechanobiology of Obesity and Related Diseases - page 204

densities) with 40 % hematocrit, the mean resistance to flow was doubled in com-
parison to pure RBC suspensions [ 85 ]. More recently, in microfluidics-based
microvascular mimics, we showed that suspensions of pseudopod-projecting neu-
trophils enhanced microchannel resistance by *15 % in the presence, but not
absence, of 10 % hematocrit [ 8 ]. Activation of neutrophils while in suspension may,
therefore, have a significant impact on microvascular blood flow.
Finally, neutrophil adhesion to non-capillary vessels (e.g., venules) may alter
microvessel resistance (Fig. 3 , Geometric effect). In addition to direct interactions
via CD11b/CD18 binding, neutrophils can also indirectly adhere to the endothe-
lium through platelets adhered on the microvessel surface during an inflammatory
response. The expression of P-selectin on the surfaces of activated platelets pro-
motes binding with neutrophils [ 72 , 87 ]. These types of interactions enable
platelets to bridge adhesive interactions between neutrophils and the endothelium
[ 88 ]. Moreover, it is possible that neutrophils may interact with other cell types
(e.g., other leukocytes, platelets, and endothelium) during the complex inflam-
matory cascade (see [ 89 ] for a complete description) that may affect microvessel
geometries with an adverse impact on microvascular resistance and flow.
Biophysically, as neutrophils adhere to, and migrate along, the vascular endo-
thelium, the cross-sectional area of the non-capillary microvasculature may be
reduced significantly to the point of altering microvascular flow resistance (Fig. 3 ).
In support of this, inflammatory stimulation has been shown to promote leukocyte
activation and adhesion in the microcirculation with an enhancing effect on
microvascular resistance [ 90 , 91 ].
Thus, changes in the morphology and surface expression profile of neutrophils
due to an activated state may profoundly impact the microcirculation. Specifically,
neutrophil activity levels are intimately linked with their rheological flow behavior
that may enhance microvascular resistance and reduce tissue perfusion. Thus,
in vivo conditions (e.g., hypercholesterolemia, hypertension, obesity) that alter
regulatory mechanisms governing the activation state of neutrophils are linked to
the state of microvascular blood flow and tissue perfusion.
4 The Shear Stress Regulation of the Neutrophil
Although neutrophil inactivity is predicated on the absence of inflammatory ago-
nists, a number of redundant cell mechanisms exist to ensure neutrophils remain
deactivated under physiological (i.e., non-inflamed, non-pathogenic) conditions. In
addition to biochemical-based control mechanisms (e.g., nitric oxide, etc.), a
growing body of evidence [ 92 , 93 ] points to mechanotransduction of hemodynamic
shear stress as a key regulatory mechanism that restricts spontaneous neutrophil