Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats.

Suematsu, Makoto; Suzuki, Hidekazu; Tamatani, Takuya; Iigou, Yutaka; DeLano, Frank A.; Miyasaka, Masayuki; Forrest, Michael J.; Kannagi, Reiji; Zweifach, Benjamin W.; Ishimura, Yuzuru; Schmid‐Schönbein, Geert W.

doi:10.1172/jci118248

Cited by 40 publications

(42 citation statements)

References 37 publications

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“…25,26 Altered leukocyte adhesion to endothelial cells has been reported in different models of hypertension and seems to be associated with changes in CAMs expression on endothelial cells, leukocytes, or both. [27][28][29][30] In our study, the initial lowaffinity leukocyte-endothelial cell interaction was attenuated in DOCA-salt rats, whereas enhanced leukocyte adhesion was observed. Decreased number of rollers may result from decreased number of leukocytes in the circulation or changes in blood flow/shear stress.…”

Section: Discussionsupporting

confidence: 50%

ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

et al. 2004

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Abstract-Leukocyte adhesion to endothelial cells plays a key role in inflammatory processes associated with end-organ injury. Endothelin-1 (ET-1), which stimulates inflammatory processes, contributes to cardiovascular damage in deoxycorticosterone (DOCA)-salt hypertension. We investigated whether ET A receptor blockade modulates in vivo leukocyte-endothelial cell interactions and expression of cell adhesion molecules (CAM) involved in these processes. DOCA-salt and control uninephrectomized rats were treated with the ET A antagonist BMS182874 (40 mg/kg per day) or vehicle. Analysis of CAMs expression by reverse transcription-polymerase chain reaction and immunohistochemistry showed increased cardiac platelet selectin (P-selectin), detected mainly in endothelial cells, and vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1 (ICAM-1), in DOCA-salt rats. Cardiac expression of endothelial selectin (E-selectin) was decreased, whereas immunoreactivity to ED-1 and myeloperoxidase (MPO) activity, markers of macrophage and leukocyte infiltration, respectively, were increased in DOCA-salt. Leukocyte-endothelial cell interaction, functionally assessed in venules of internal spermatic fascia by intravital microscopy, was significantly altered in DOCA-salt rats as evidenced by increased leukocyte adhesion and decreased rolling. BMS182874 treatment normalized leukocyte-endothelium interactions, decreased cardiac VCAM-1 expression in DOCA and control groups, and had no effects on ICAM-1 expression. BMS182874 also increased E-selectin and abolished P-selectin expression in DOCA-salt, but not in control rats. The ET A antagonist reduced cardiac ED-1 content and MPO activity and prevented cardiac damage in DOCA-salt rats. These data indicate that ET-1 participates, via activation of ET A receptors, in altered leukocyte-endothelial cell interactions in DOCA-salt rats, possibly by modulating expression of CAMs, and that the inflammatory status is associated with cardiac damage in mineralocorticoid hypertension.

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Section: Discussionsupporting

confidence: 50%

ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

et al. 2004

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“…Such degranulation was observed previously in the spontaneously hypertensive rats, possibly because of prolonged circulation time in light of a P-selectin deficiency, that is, in hypertension, older PMN may not be properly removed from the circulation because of an adhesion deficiency. 1,11,32 We know that the granulocyte activation is accompanied by an increase of the cytosolic Ca 2ϩ content, [33][34][35][36] and in our research this finding is constantly present.…”

Section: Discussionmentioning

confidence: 53%

Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca ²⁺ Content After Activation in Essential Hypertension

et al. 2000

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Abstract-The purpose of this research was to obtain further information about the role of polymorphonuclear leukocytes in essential hypertension. These cells could be involved in the pathogenesis of organ injury. Thirty subjects (14 men and 16 women) with essential hypertension were enrolled. In these subjects we determined, at baseline and after in vitro activation with 4-phorbol 12-myristate 13-acetate and N-formyl-methionyl-leucyl-phenylalanine, the polymorphonuclear leukocyte membrane fluidity, obtained by labeling the cells with 1-[4-(trimethylamino)phenyl]-6-phenyl-1,3,5-hexatriene, cytosolic Ca 2ϩ concentration, obtained by marking the cells with Fura 2-AM, and integrin pattern (CD11a, CD11b, CD11c, and CD18), by using the indirect immunofluorescence with a flow cytometer. At baseline there was no difference in membrane fluidity between normal subjects and hypertensives, whereas hypertensives showed an increase in cytosolic Ca 2ϩ content and an increase of the phenotypical expression of CD11a, CD11b, and CD18. In normal subjects and in hypertensives, after activation, no variation was found in membrane fluidity and cytosolic Ca 2ϩ content. In normal subjects, after activation, we observed a significant increase of the expression of all adhesion molecules, whereas in hypertensives we found an increase of the expression of CD11b, CD11c, and CD18 but also a decrease of CD11a. The behavior of the polymorphonuclear leukocyte integrin profile may have several explanations, and in particular, the trend of CD11a after chemotactic activation may be related to its cleavage or to an altered integrin phosphorylation/dephosphorylation balance hypothetically present in this clinical condition. Key Words: hypertension, essential Ⅲ neutrophils Ⅲ integrins Ⅲ membranes Ⅲ calcium I n recent years, the knowledge about hypertensive disease was enriched by much evidence regarding the role of circulating leukocytes. In fact, from observations of an altered leukocyte count in experimental and clinical hypertension, 1-5 some authors hypothesized that leukocytes could be activated and that this condition, strengthened by nitrobule tetrazolium (NBT) reduction test, could contribute to explaining organ injury. 6 -11 In our previous works, 12,13 we evaluated, in essential hypertension, the leukocyte rheology, expressed as flow properties, polymorphonuclear leukocyte (PMN) membrane fluidity and PMN cytosolic Ca 2ϩ content at baseline and after chemotactic activation.Subsequently, our aim was to examine, in hypertensives, the PMN adhesion molecule profile. Our interest in this topic, for which there is little information in the literature, is derived from the fact that some experimental data underline how in this clinical condition an abnormality of the leukocyte adhesion is present. 9 -11,14 As we know, adhesion is particularly mediated by integrins; among these, ␤ 2 integrins (CD11a, CD11b, CD11c, CD18) are very important.Integrins 15,16 are usually in a low-affinity state that makes them unable to interact with their corresponding...

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“…The SHR exhibits CD18 receptor cleavage, and levels of the cell adhesion molecule, P-selectin, are lower on the post-capillary venules (4). Such features impair leukocyte adhesion to the postcapillary endothelium in the SHR (34) and produce a larger number of circulating leukocytes (5).…”

Section: Discussionmentioning

confidence: 99%

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

Chen

DeLano

Valdez

et al. 2010

American Journal of Physiology-Cell Physiology

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Physiological fluid shear stress evokes pseudopod retraction in normal leukocytes by a mechanism that involves the formyl peptide receptor (FPR) as mechanosensor. In hypertensives, such as the spontaneously hypertensive rat (SHR), leukocytes lack the normal fluid shear response. The increased activity of matrix metalloproteinases (MMPs, including MMP-9) in SHR plasma is associated with cleavage of several cell membrane receptors. We hypothesize that the attenuated fluid shear response in leukocytes (neutrophils) of the SHR is due to extracellular proteolytic cleavage of the 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 with neutrophils of control Wistar-Kyoto (WKY) rats. SHR neutrophils and naïve Wistar rat neutrophils exposed to SHR plasma also exhibited impaired fluid shear responses as shown by their inability to project pseudopods with fluid shear. Labeling of extracellular FPR revealed that the FPR density in SHR neutrophils is on average 27% reduced compared with those of the WKY rats. Exposure of Wistar rat neutrophils to the gelatinase MMP-9 (final concentration 5 nM) led to attenuation of fluid shear response and decrease in extracellular FPR density. Chronic treatment of the SHR with a broad-acting MMP inhibitor, doxycycline, significantly improved the fluid shear response and increased the FPR extracellular density of SHR neutrophils. These results suggest that proteolytic cleavage of the FPR may interfere with normal fluid shear-induced pseudopod retractions in SHR neutrophils.formyl peptide receptor; pseudopod projection; cone-and-plate device; N-formyl-methionine-leucine-phenylalanine; immunohistochemistry ONE OF THE FEATURES OF LEUKOCYTE stimulation by N-formylMet-Leu-Phe (fMLP) is the projection of pseudopods by Factin polymerization (8,41). In a normal circulation, the majority of leukocytes have few or no pseudopods, an effect mediated by fluid shear stress with retraction of pseudopods (14,26). However, an increased number of circulating leukocytes project pseudopods in the circulation of hypertensives, such as the spontaneously hypertensive rat (SHR), with elevated microvascular resistance (9). The impaired movement of such neutrophils with pseudopods through capillaries causes substantial elevation of hemodynamic resistance in the SHR (9). Currently, the mechanism by which an increased number of pseudopods form on circulating neutrophils of the SHR under normal physiological fluid shear is unexplored.Recently, G protein-coupled receptors, such as the formyl peptide receptor (FPR) in the case of neutrophils, have been shown to serve as mechanosensors for fluid shear stress (21). Exhibiting high constitutive activity, the FPR binding target for N-formyl chemoattractants is predominantly expressed on neutrophils and monocytes (15, 21). Herein we are interested in investigating the fluid shear response of neutrophils of ...

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Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats.

Cited by 40 publications

References 37 publications

ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca ²⁺ Content After Activation in Essential Hypertension

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

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Impairment of selectin-mediated leukocyte adhesion to venular endothelium in spontaneously hypertensive rats.

Cited by 40 publications

References 37 publications

ET A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

ET A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca 2+ Content After Activation in Essential Hypertension

Receptor cleavage reduces the fluid shear response in neutrophils of the spontaneously hypertensive rat

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ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

ET _A Receptor Mediates Altered Leukocyte-Endothelial Cell Interaction and Adhesion Molecules Expression in DOCA–Salt Rats

Polymorphonuclear Integrins, Membrane Fluidity, and Cytosolic Ca ²⁺ Content After Activation in Essential Hypertension