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Biomedical subjects

Geert W Schmid-Schönbein

Publications and source records attributed to Geert W Schmid-Schönbein.

At least 19 recordsLinked to original sources
PubMed2007

C-reactive protein, an 'intermediate phenotype' for inflammation: human twin studies reveal heritability, association with blood pressure and the metabolic syndrome, and the influence of common polymorphism at catecholaminergic/beta-adrenergic pathway loci.

BACKGROUND: C-reactive protein (CRP) both reflects and participates in inflammation, and its circulating concentration marks cardiovascular risk. Here we sought to understand the role of heredity in determining CRP secretion. METHODS: CRP, as well as multiple facets of the metabolic syndrome, were measured in a series of 229 twins, both monozygotic (MZ) and dizygotic (DZ), to estimate trait heritability (h2). Single nucleotide polymorphism (SNP) genotyping was done at adrenergic pathway loci. Haplotypes were inferred from genotypes by likelihood methods. Association of CRP with hypertension and the metabolic syndrome was studied in a larger series of 732 individuals, including 79 with hypertension. RESULTS: MZ and DZ twin variance components indicated substantial h2 for CRP, at approximately 56 +/- 7% (P < 0.001). CRP was significantly associated (P < 0.05) with multiple features of the metabolic syndrome in twins, including body mass index (BMI), blood pressure (BP), leptin and lipids. In established hypertension, elevated CRP was associated with increased BP, BMI, insulin, HOMA (index of insulin resistance), leptin, triglycerides and norepinephrine. Twin correlations indicated pleiotropy (shared genetic determination) for CRP with BMI (P = 0.0002), leptin (P < 0.001), triglycerides (P = 0.002) and systolic blood pressure (SBP) (P = 0.042). Approximately 9800 genotypes (43 genetic variants at 17 loci) were scored within catecholaminergic pathways: biosynthetic, receptor and signal transduction. Plasma CRP concentration in twins was predicted by polymorphisms at three loci in physiological series within the catecholamine biosynthetic/beta-adrenergic pathway: TH (tyrosine hydroxylase), ADRB1 (beta1-adrenergic receptor) and ADRB2 (beta2-adrenergic receptor). In the TH promoter, common allelic variation accounted for up to approximately 6.6% of CRP inter-individual variance. At ADRB1, variation at Gly389Arg predicted approximately 2.8% of CRP, while ADRB2 promoter variants T-47C and T-20C also contributed. Particular haplotypes and diplotypes at TH and ADRB1 also predicted CRP, though typically no better than single SNPs alone. Epistasis (gene-by-gene interaction) was demonstrated for particular combinations of TH and ADRB2 alleles, consistent with their actions in a pathway in series. In an illustration of pleiotropy, not only CRP but also plasma triglycerides were predicted by polymorphisms at TH (P = 0.0053) and ADRB2 (P = 0.027). CONCLUSIONS: CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting.

Adult↗
PubMed2006

Intrinsic disturbance of cellular redox balance enhances blood lymphocyte apoptosis in the spontaneously hypertensive rat.

The spontaneously hypertensive rat (SHR) shows an altered cell apoptosis rate compared to normotensive controls by a mechanism that may involve redox imbalance. This study was designed to determine whether cellular oxidative stress and apoptosis in blood lymphocytes are enhanced in the SHR by intrinsic cellular abnormalities and/or by factors derived from selected organs (kidney, adrenals). We identified apoptosis and free radical production in isolated peripheral blood lymphocytes with flow cytometry before and after serum withdrawal, which exposes the cells to a pro-oxidative condition. Freshly drawn SHR lymphocytes showed higher levels of apoptosis and intracellular oxygen radicals than lymphocytes from normotensive Wistar-Kyoto rats (p < 0.05). Apoptosis and intracellular oxygen radicals were profoundly elevated after serum-free incubation in SHR cells and to a lesser extent in normotensive controls suspended in exactly the same medium (p < 0.01, SHR vs normotensives). Cell-permeable antioxidants, L-cysteine and Tempol, attenuated serum deprivation-induced apoptosis as well as cellular oxidative stress. Blood plasma and organ extracts from the SHR exerted pro- or antiapoptotic activity to the same degree as those from normotensives. The results suggest that blood lymphocyte apoptosis is enhanced in the SHR due to intrinsically disturbed cellular redox balance rather than altered activity in extracellular humoral factors.

Aging↗
PubMed2006

G protein-coupled receptors serve as mechanosensors for fluid shear stress in neutrophils.

Many cells respond to fluid shear stress but in a cell type-specific fashion. Fluid shear stress applied to leukocytes serves to control pseudopod formation, migration, and other functions. Specifically, fresh neutrophils or neutrophilic leukocytes derived from differentiated HL60 cells respond to fluid shear stress by cytoplasmic pseudopod retraction. The membrane elements that sense fluid shear and induce such a specific response are still unknown, however. We hypothesized that membrane receptors may serve as fluid shear sensors. We found that fluid shear decreased the constitutive activity of G protein-coupled receptors (GPCRs). Inhibition of GPCR constitutive activity by inverse agonists abolished fluid shear stress-induced cell area reduction. Among the GPCRs in neutrophils, the formyl peptide receptor (FPR) exhibits relatively high constitutive activity. Undifferentiated HL60 cells that lacked FPR formed few pseudopods and showed no detectable response to fluid shear stress, whereas expression of FPR in undifferentiated HL60 cells caused pseudopod projection and robust pseudopod retraction during fluid shear. FPR small interfering RNA-transfected differentiated HL60 cells exhibited no response to fluid shear stress. These results suggest that GPCRs serve as mechanosensors for fluid shear stress in neutrophils by decreasing its constitutive activity and reducing pseudopod projection.

Cell Differentiation↗
PubMed2006

Intraluminal pancreatic serine protease activity, mucosal permeability, and shock: a review.

Shock states are characterized by a pronounced activation of numerous cell types that lead to an acute inflammatory reaction. The exact mechanism by which these inflammatory cells are activated is not known. Numerous studies have implicated the gastrointestinal tract as one of the main sites for the generation of inflammatory mediators and initiation of an acute systemic response. The pancreas is known to secrete powerful digestive enzymes, and we hypothesize that they may play a leading role in the pathogenesis of multiorgan failure after the onset of shock. We carried out a search in PubMed for all relevant studies related to the role of the pancreas in shock. Studies that included information concerning the role of pancreatic enzymes in shock were then summarized. Our article serves to review the current hypotheses on how digestive enzymes produced by the pancreas may play a pivotal role in initiating the systemic inflammatory response. We further hypothesize how these enzymes and/or their products may ultimately contribute to multiorgan failure and death.

Animals↗
PubMed2006

Analysis of inflammation.

In the past, inflammation has been associated with infections and with the immune system. But more recent evidence suggests that a much broader range of diseases have telltale markers for inflammation. Inflammation is the basic mechanism available for repair of tissue after an injury and consists of a cascade of cellular and microvascular reactions that serve to remove damaged and generate new tissue. The cascade includes elevated permeability in microvessels, attachment of circulating cells to the vessels in the vicinity of the injury site, migration of several cell types, cell apoptosis, and growth of new tissue and blood vessels. This review provides a summary of the major microvascular, cellular, and molecular mechanisms that regulate elements of the inflammatory cascade. The analysis is largely focused on the identification of the major participants, notably signaling and adhesion molecules, and their mode of action in the inflammatory cascade. We present a new hypothesis for the generation of inflammatory mediators in plasma that are derived from the digestive pancreatic enzymes responsible for digestion. The inflammatory cascade offers a large number of opportunities for development of quantitative models that describe various aspects of human diseases.

Animals↗
PubMed2006

Chronotropic response of cultured neonatal rat ventricular myocytes to short-term fluid shear.

Ventricular myocytes are continuously exposed to fluid shear in vivo by relative movement of laminar sheets and adjacent cells. Preliminary observations have shown that neonatal myocytes respond to fluid shear by increasing their beating rate, which could have an arrhythmogenic effect under elevated shear conditions. The objective of this study is to investigate the characteristics of the fluid shear response in cultured myocytes and to study selected potential mechanisms. Cultured neonatal rat ventricular myocytes that were spontaneously beating were subjected to low shear rates (5-50/s) in a fluid flow chamber using standard culture medium. The beating rate was measured from digital microscopic recordings. The myocytes reacted to low shear rates by a graded and reversible increase in their spontaneous beating rate of up to 500%. The response to shear was substantially attenuated in the presence of the beta-adrenergic agonist isoproterenol (by 86+/-8%), as well as after incubation with integrin-blocking RGD peptides (by 92+/-8%). The results suggest that the beta-adrenergic signaling pathway and integrin activation, which are known to interact, may play an important role in the response mechanism.

Action Potentials↗
PubMed2005

The influence of fluid shear stress on the remodeling of the embryonic primary capillary plexus.

The primary capillary plexus in early yolk sacs is remodeled into matured vitelline vessels aligned in the direction of blood flow at the onset of cardiac contraction. We hypothesized that the influence of fluid shear stress on cellular behaviors may be an underlying mechanism by which some existing capillary channels remain open while others are closed during remodeling. Using a recently developed E-Tmod knock-out/lacZ knock-in mouse model, we showed that erythroblasts exhibited rheological properties similar to those of a viscous cell suspension. In contrast, the non-erythroblast (NE) cells, which attach among themselves within the yolk sac, are capable of lamellipodia extension and cell migration. Isolated NE cells in a parallel-plate flow chamber exposed to fluid shear stress, however, ceased lamellipodia extension. Such response may minimize NE cell migration into domains exposed to fluid shear stress. A two-dimensional mathematical model incorporating these cellular behaviors demonstrated that shear stress created by the blood flow initiated by the embryonic heart contraction might be needed for the remodeling of primary capillary plexus.

Animals↗
PubMed2005

Oxidative stress promotes endothelial cell apoptosis and loss of microvessels in the spontaneously hypertensive rats.

OBJECTIVE: Endothelial cell apoptosis caused by oxidative stress may lead to the loss of microvessels (rarefaction) in hypertension. We examine here the effects of antioxidants on cell apoptosis and rarefaction. METHODS AND RESULTS: The juvenile spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with superoxide scavengers, Tempol or Tiron, during growth. After the treatment, oxidative stress status, endothelial cell apoptosis rate, and microvessel length density in skeletal muscle and mesentery were evaluated in comparison with age-matched controls. Untreated 16-week-old SHR had higher oxidative stress (P<0.01) and cell apoptosis rate (P<0.05) and lower microvessel length density (371+/-17 mm/mm3 [P<0.01]) compared with age-matched WKY rats (435+/-15 mm/mm3). In the SHR, but not in WKY rats, systemically applied antioxidants attenuated oxidative stress and cell apoptosis rate (P<0.05 versus untreated controls) and prevented the loss of microvessels (411+/-15 mm/mm3 for Tempol [P<0.01 versus untreated control] and 399+/-17 mm/mm3 for Tiron [P<0.05]). CONCLUSIONS: Antioxidant treatment with cell-permeable superoxide scavengers inhibits endothelial cell apoptosis and prevents microvessel rarefaction in the SHR during growth.

Animals↗
PubMed2005

Activated leukocytes and endothelial cells enhance retention of ultrasound contrast microspheres containing perfluoropropane in inflamed venules.

PURPOSE: To characterize the flow dynamics of albumin ultrasound contrast microspheres containing perfluoropropane (PFP) in normal and inflamed microvasculature. MATERIALS AND METHODS: Mesenteric microvessels of rats were examined after an intravenous injection of fluorocein-labeled erythrocytes or PFP microspheres by fluorescence intravital microscopy with and without local application of 10(-8) M platelet activating factor (PAF) as an experimental form of inflammation. RESULTS: All the microspheres passed freely through arterioles and capillaries. Mean velocities of the microspheres in each vessel were closely correlated with those of erythrocytes. Only a minor fraction of the microspheres was retained in the venules (> or =0.1 s stoppage) by attachment to endothelial cells. The frequency of microsphere retention in venules was significantly enhanced by PAF (2.6+/-2.1%, P<0.01 vs. control), especially in regions with leukocyte adhesion. Treatment with a monoclonal antibody to intercellular adhesion molecule-1, P-selectin or the common leukocyte antigen inhibited PAF-induced microsphere retention in venules (P<0.05). In the inflamed microcirculation, a small subgroup of microspheres becomes attached to venular endothelial cells in regions with leukocyte adhesion via interaction among microspheres, activated leukocytes and endothelial cells via adhesion molecules. CONCLUSION: In inflamed microcirculation, a small subgroup of microspheres becomes attached to venular endothelial cells in regions with leukocyte adhesion via interaction among microspheres, activated leukocytes and endothelial cells via adhesion molecules. These results suggest that ultrasonography with microspheres has the potential to evaluate inflammatory site distribution as well as tissue perfusion.

Animals↗
PubMed2005

Transport processes in biomedical systems: a roadmap for future research directions.

A workshop was convened at Bethesda, Maryland on May 5 and 6, 2004 under the sponsorship of the NSF and NIH with the objectives of identifying emerging intellectual opportunities and applications in biotransport sciences and of guiding future research in the field. Approximately 50 leading researchers in the fields of fluid, heat, and mass biotransport were presented forward-looking perspectives and discussed how to synthesize broad cross-disciplinary areas: this defined guidelines for a roadmap document. Applications were presented in the context of disease analysis and diagnosis, therapy and prevention, and for physiologic and engineered living systems. The roadmap prioritizes specific research thrusts that reflect projected impacts on intellectuals, medical, and biological advances. Several overarching themes emerged. Most central is the expanded integration of fundamental transport sciences into the understanding of living systems and the great potential of patient specific modeling in designing a broad array of medical procedures.

Biological Transport↗
PubMed2005

De-activation of neutrophils in suspension by fluid shear stress: a requirement for erythrocytes.

Leukocyte de-activation in response to a mechanical stimulus may be an important mechanism to reduce inflammation in the circulation and cardiovascular complications. We examine here a specific form of leukocyte activation in the form of pseudopod projection, a process that is important during cell spreading and migration, but if it occurs in circulating leukocytes, may also lead to their entrapment in the microvascular network. Fresh neutrophils were activated with fMLP, suspended without adhesion to endothelium, and sheared in a cone-and-plate device while both shear stress and shear rate were measured. A fraction of the activated neutrophils retracted their pseudopods under the influence of fluid shear and returned to round shape. Pseudopod retraction was observed only in the presence of erythrocytes (at shear stresses up to approximately 25 dyn/cm(2)). At a constant hematocrit and increasing plasma viscosities with addition of macromolecules, the number of de-activated neutrophils scaled with shear stress and less so with shear rate. We examined a biochemical and rheological role of erythrocytes during shear de-activation of neutrophils. Addition of superoxide dismutase (SOD) in phosphate buffer served to enhance neutrophil de-activation by fluid shear. Replacement of erythrocytes by solid microspheres (5.4 mum) to simulate the particle properties of the erythrocytes, did not serve to enhance neutrophil de-activation unless in the presence of SOD. At higher shear stresses without erythrocytes (38-77 dyn/cm(2)), we also observed neutrophil de-activation but only in the presence of SOD. These results suggest that erythrocytes play an important role in neutrophil de-activation by reducing the superoxide level in plasma. Shear stress, rather than shear rate, is the key determinant that regulates neutrophil de-activation.

Animals↗
PubMed2005

Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension.

Genetic studies of essential hypertension, a complex, polygenic, and age-dependent disorder, have not been able to completely elucidate the genes responsible for development of the trait. We used a novel strategy to compare gene expression in the adrenal gland of two independent rodent models of human essential hypertension (the spontaneously hypertensive rat, SHR, and the blood pressure high mouse, BPH), with the goal of uncovering shared, common genetic mechanisms of hypertension across mammalian species that might, therefore, be pertinent to human hypertension. We deliberately studied young, 4- to 5-week-old, "prehypertensive" SHR and BPH that had not yet developed complete elevations in blood pressure (BP), so that we could minimize the impact of chronic, sustained BP elevation, age, and other confounding factors on gene expression, therefore increasing the likelihood that differential expression reflects relatively early pathogenic mechanisms in hypertension, rather than later responses to, or compensations for BP elevation. We compared transcript expression patterns of genes orthologous between the rat and the mouse, and presented candidate genes for hypertension that are differentially expressed in the same direction in SHR and BPH (ie, overexpressed in both SHR and BPH, or underexpressed in both SHR and BPH). Then we used a systems biology approach to analyze expression patterns in biochemical pathways and networks to isolate systems involved in hypertension pathology in both SHR and BPH. We found transcript pattern evidence for involvement of several systems in the pathology of hypertension in SHR and BPH: adrenal catecholamines and sympathetic function; steroid hormone synthesis, catabolism, and its contribution to enhanced glucocorticoid sensitivity in SHR; oxidative stress and its role as a common mechanism of vascular and end-organ injury; and intermediary metabolism with global but mechanistically different perturbations in SHR and BPH. Approximately 10% of the differentially expressed orthologous genes we studied shared a common direction of expression in the two hypertensive rodent strains, suggesting fundamental transcriptional mechanisms in common whereby mammals can elevate BP or respond to such elevation; even these shared orthologs spanned a diverse set of biological processes, reinforcing the multifactorial and complex nature of hypertension.

Adrenal Glands↗
PubMed2005

An animal model of venous hypertension: the role of inflammation in venous valve failure.

BACKGROUND: Clinical observation suggests that chronic venous insufficiency is related to failure of venous valves. Duplex ultrasound studies of lower extremity superficial veins regularly show valve failure and venous reflux. Gross morphologic observation of venous valves in surgical specimens shows tearing, splitting, scarring, and disappearance of valves. HYPOTHESIS: Venous valve damage is acquired, linked with venous hypertension, and affected by inflammation. OBJECTIVE: The objective of this study was to investigate the inflammatory process in valve remodeling associated with acute and chronic venous hypertension. METHODS: A femoral arteriovenous fistula was created in study animals (Wistar rats, n = 60), and animals without an arteriovenous fistula were studied as controls (n = 5). At 1, 7, 21, and 42 days animals with the femoral arteriovenous fistula were anesthetized, and systemic pressure, the pressure in the femoral vein distal to fistula, and the pressure of the femoral vein in the contralateral hind limb were measured. Timed collection of blood backflow after division of the femoral vein distal to the fistula and in the alive, anesthetized animal was collected, measured, and calculated per unit time to be used as an indicator of valve insufficiency. The femoral vein distal to the fistula was harvested; valvular structures were examined and measured. Specimens were processed, and longitudinal sections were made and challenged with immunostaining antibodies against matrix metalloprotease (MMP)-2 and MMP-9. Sections were examined, and expression of molecular markers was determined by light absorption measurements after image digitization. RESULTS: One week after the procedure, all animals exhibited some degree of hind limb edema ipsilateral to the arteriovenous fistula. Pressure in the femoral vein distal to the fistula was markedly increased on average to 96 +/- 9 mm Hg. Reflux was increased in a time-dependent manner, with the 21-day and 42-day groups showing the highest values. Valves just distal to the fistula showed an increased diameter of the valvular annulus and a shortening of the annular height. Venous wall findings included fibrosis and fusion of the media and adventitia and scarring and disappearance of valves principally in the 21- and 42-day specimens. Immunolabeling for MMP-2 showed an increased level in the 21- and 42-day groups. MMP-9 showed an increased level at 1 day, followed by a more marked level in the 21- and 42-day groups. CONCLUSIONS: In this animal model of venous hypertension the findings of limb edema, increasing valvular reflux, and morphologic changes of increased annulus diameter and valve height are seen. Histologic changes included massive fibrosis of media and fusion with adventitia. Inflammatory markers MMP-2 and MMP-9 are strongly represented, and valve disappearance occurs after these markers are present. The gross morphologic changes seen are quite similar to those observed in human surgical specimens removed in treatment of venous insufficiency. CLINICAL RELEVANCE: When observed angioscopically at the time of vein stripping, saphenous vein valves show severe deformities including shortening, scarring, and tearing. The current model of induced venous hypertension demonstrates early venous valve changes that replicate those observed in humans. This observation provides a link from venous hypertension to an induced inflammatory reaction that stimulates the valve damage. Thus the model could be useful for defining the fundamental mechanisms that cause venous valve failure and varicose veins and in pharmacologic testing to prevent or treat venous insufficiency.

Animals↗
PubMed2005

Mechanics of curved plasma membrane vesicles: resting shapes, membrane curvature, and in-plane shear elasticity.

Highly curved cell membrane structures, such as plasmalemmal vesicles (caveolae) and clathrin-coated pits, facilitate many cell functions, including the clustering of membrane receptors and transport of specific extracellular macromolecules by endothelial cells. These structures are subject to large mechanical deformations when the plasma membrane is stretched and subject to a change of its curvature. To enhance our understanding of plasmalemmal vesicles we need to improve the understanding of the mechanics in regions of high membrane curvatures. We examine here, theoretically, the shapes of plasmalemmal vesicles assuming that they consist of three membrane domains: an inner domain with high curvature, an outer domain with moderate curvature, and an outermost flat domain, all in the unstressed state. We assume the membrane properties are the same in these domains with membrane bending elasticity as well as in-plane shear elasticity. Special emphasis is placed on the effects of membrane curvature and in-plane shear elasticity on the mechanics of vesicle during unfolding by application of membrane tension. The vesicle shapes were computed by minimization of bending and in-plane shear strain energy. Mechanically stable vesicles were identified with characteristic membrane necks. Upon stretch of the membrane, the vesicle necks disappeared relatively abruptly leading to membrane shapes that consist of curved indentations. While the resting shape of vesicles is predominantly affected by the membrane spontaneous curvatures, the membrane shear elasticity (for a range of values recorded in the red cell membrane) makes a significant contribution as the vesicle is subject to stretch and unfolding. The membrane tension required to unfold the vesicle is sensitive with respect to its shape, especially as the vesicle becomes fully unfolded and approaches a relative flat shape.

Computer Simulation↗
PubMed2004

Control of neutrophil pseudopods by fluid shear: role of Rho family GTPases.

Blood vessels and blood cells are under continuous fluid shear. Studies on vascular endothelium and smooth muscle cells have shown the importance of this mechanical stress in cell signal transduction, gene expression, vascular remodeling, and cell survival. However, in circulating leukocytes, shear-induced signal transduction has not been investigated. Here we examine in vivo and in vitro the control of pseudopods in leukocytes under the influence of fluid shear stress and the role of the Rho family small GTPases. We used a combination of HL-60 cells differentiated into neutrophils (1.4% dimethyl sulfoxide for 5 days) and fresh leukocytes from Rac knockout mice. The cells responded to shear stress (5 dyn/cm2) with retraction of pseudopods and reduction of their projected cell area. The Rac1 and Rac2 activities were decreased by fluid shear in a time- and magnitude-dependent manner, whereas the Cdc42 activity remained unchanged (up to 5 dyn/cm2). The Rho activity was transiently increased and recovered to static levels after 10 min of shear exposure (5 dyn/cm2). Inhibition of either Rac1 or Rac2 slightly but significantly diminished the fluid shear response. Transfection with Rac1-positive mutant enhanced the pseudopod formation during shear. Leukocytes from Rac1-null and Rac2-null mice had an ability to form pseudopods in response to platelet-activating factor but did not respond to fluid shear in vitro. Leukocytes in wild-type mice retracted pseudopods after physiological shear exposure, whereas cells in Rac1-null mice showed no retraction during equal shear. On leukocytes from Rac2-null mice, however, fluid shear exerted a biphasic effect. Leukocytes with extended pseudopods slightly decreased in length, whereas initially round cells increased in length after shear application. The disruption of Rac activity made leukocytes nonresponsive to fluid shear, induced cell adhesion and microvascular stasis, and decreased microvascular density. These results suggest that deactivation of Rac activity by fluid shear plays an important role in stable circulation of leukocytes.

Animals↗
PubMed2004

Contribution of fluid shear response in leukocytes to hemodynamic resistance in the spontaneously hypertensive rat.

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. The high incidence of circulating leukocytes with pseudopods results in slower cell passage through capillaries under normal blood flow and during reduced flow enhanced capillary plugging both in vivo and in vitro. SHR blood requires higher pressure (90.0+/-8.2 mm Hg) than Wistar Kyoto rat (WKY, 69.6+/-6.5 mm Hg; P<0.0001) or adrenalectomized SHR (73.5+/-2.1 mm Hg; P=0.0009) at the same flow rate in the resting hemodynamically isolated skeletal muscle microcirculation. Intravenous injection of blood from SHR, but not WKY, causes blood pressure increase in normal rats, which depends on pseudopod formation. We conclude that in addition to enhanced vascular tone, pseudopod formation with lack of normal fluid shear response may serve as mechanisms for an elevated hemodynamic resistance in SHR.

Animals↗
PubMed2004

Leukocyte fluid shear response in the presence of glucocorticoid.

Leukocytes respond to physiological fluid shear stress ( approximately 1.5 dyn/cm(2)) by cytoplasmic reorganization. The cytoplasm is also influenced, however, by glucocorticoids. In this study, we explore how glucocorticoids may affect the leukocyte fluid shear response. Normal leukocytes, exposed to fluid shear in vitro during active migration, retract pseudopods accompanied by modestly decreasing intracellular calcium ions. In contrast, dexamethasone (DX)-treated leukocytes project pseudopods after shear exposure with a significant rise in intracellular calcium ions, an effect that can be blocked by voltage-dependent calcium channel blockers. Although a cyclic adenine monophosphate analog blocks calcium influx and pseudopod projection by DX, inhibition of A-kinase induces reversal of the shear response, as seen with DX treatment. DX also reverses the leukocyte shear response in vivo in the rat circulation. Leukocytes that adhere to the endothelium in postcapillary venules of control rats return into the circulation only after pseudopod retraction, and in DX-treated rats, adherent leukocytes return into the circulation still with projecting pseudopods. The fraction of circulating leukocytes with pseudopods in DX-treated rats is higher than in controls. Thus, the reversal of leukocyte shear response by glucocorticoids may contribute to an enhanced incidence of circulating leukocytes with pseudopods, a process that affects the kinetics of these cells in the microcirculation.

A Kinase Anchor Proteins↗