Contribution of Fluid Shear Response in Leukocytes to Hemodynamic Resistance in the Spontaneously Hypertensive Rat

Abstract

Abstract-The mechanisms for elevation of peripheral vascular resistance in spontaneously hypertensive rats (SHR), a glucocorticoid-dependent form of hypertension, are unresolved. An increase in hemodynamic resistance caused by circulating blood may be a factor. Physiological fluid shear stress induces a variety of responses in circulating leukocytes, including pseudopod retraction. Due to high rigidity, leukocytes with pseudopods have greater difficulty to pass through capillaries. Because SHR have more circulating leukocytes with pseudopods, we hypothesize that inhibition of the leukocyte shear response by glucocorticoids in SHR impairs normal leukocyte passage through capillaries and causes enhanced resistance in capillary channels. Fluid shear leads to retraction of pseudopods in normal leukocytes, whereas shear induces pseudopod projection in SHR and dexamethasone-treated Wistar rats.

Chapter 12 Structure of Microvascular Networks in Genetic Hypertension

“…In the spontaneously hypertensive rat (SHR), which represents a model of hypertension with a genetic background, the microcirculation is characterized by smooth muscle medial hyperplasia, smooth muscle hypertrophy, enhanced smooth muscle longitudinal coverage, enhanced microvessel specific oxidative stress, elevated counts of activated circulating leukocytes, enhanced capillary flow resistance, impairment of selectin-mediated leukocyte adhesion, and extensive non-uniform endothelial cell apoptosis (Suematsu et al, 2002;Fukuda et al, 2004). These characteristics represent a complex remodeling scenario across multiple scales.…”

Linking the Pathobiology of Hypercholesterolemia with the Neutrophil Mechanotransduction

“…What may change and contribute to "abnormal" behavior is their sensitivity to the surrounding fluid flow mechanoenvironment with a negative impact on the ability of fluid shear stress to deactivate the neutrophils. Along this line, the work of Geert SchmidSchönbein at the University of California, San Diego has demonstrated that attenuated neutrophil shear responses contribute to the microvascular pathobiology observed in spontaneously hypertensive rats (SHRs) [110] and, in doing so, illustrated the potential impact of impaired shear stress mechanotransduction on cardiovascular health.…”

“…Although the increased activity of neutrophils is not associated with increased adhesion to microvascular endothelium [78], their increased numbers raise peripheral vascular resistance [110]. One possible explanation is that circulating activated neutrophils in SHRs release vasoactive substances that constrict the small arteries and arterioles; this has been documented for atherosclerosis [114][115][116].…”

“…Extensive evidence, however, points to a hemorheological effect of leukocyte activation on microvascular resistance [1,34,36]. Specifically, the disturbed motion of white blood cells, due to pseudopod projection, significantly reduces erythrocyte velocities in the microcirculation increasing hemodynamic resistance and upstream blood pressures [36,110] (see Figure 1).…”

“…The key evidence for the involvement of fluid flow mechanotransduction in microvascular abnormalities due to hypertension is that neutrophils from SHRs lack the ability to retract pseudopods in response to shear stress; in some cases, cells extend cellular projections under flow stimulation [110]. 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 SHRs on the plasma level of glucocorticoid-related steroid hormones and the density of glucocorticoid receptors on the neutrophil surface [117,118].…”