Attenuation of Fluid Shear Response by Proteolytic Cleavage of the Formyl Peptide Receptor on Neutrophils of the Spontaneously Hypertensive Rat

When subject to physiological fluid shear, normal circulating leukocytes retract pseudopods by a mechanism that utilizes the formyl peptide receptor (FPR) as mechanosensor. In line with their increased activity of several plasma matrix‐metalloproteinases and cleavage of several key membrane receptors, leukocytes of the Spontaneously Hypertensive Rat (SHR) have an impaired fluid shear response. This phenomenon affects leukocyte functions such as those manifest in SHR capillary hemodynamic resistance. We hypothesize that the attenuated fluid shear response in SHR neutrophils is due to proteolytic cleavage of extracellular FPR. We show that suspended SHR neutrophils in whole blood sheared in a cone‐and‐plate device or individual neutrophils adherent to a glass surface and subject to fluid shear exhibited reduced pseudopod retractions compared to neutrophils of control Wistar Kyoto (WKY) rats. Labeling of extracellular FPR revealed that the FPR density in SHR neutrophils is on average 27% reduced compared to those of WKY rats. Chronic treatment of the SHR with a broad‐acting MMP inhibitor, doxycycline, significantly improved the fluid shear response and increased the extracellular FPR density of SHR neutrophils. These results suggest that proteolytic cleavage of FPR interferes with normal fluid shear‐induced pseudopod retractions in SHR neutrophils.