Biomedical subjects

Axel R Pries

Publications and source records attributed to Axel R Pries.

17 recordsLinked to original sources

PubMed2006

Arteriolar blood flow pulsatility in a patient before and after implantation of an axial flow pump.

In a patient with end stage ischemic heart failure scheduled for implantation of an axial flow pump small arteriolar flow pattern was recorded using a novel intravital microscope. Preoperative arteriolar blood flow velocity was highly pulsatile, ranging from about 7 to 16 mm per second in a 12.8 microm diameter arteriole. After implantation of the pump, this pulsatility was abrogated and arteriolar blood flow velocity changed instantaneously with changes in pump speed (eg, 2 mm/s at 5,000 rpm vs 3.5 mm/s at 8,000 rpm in an 8.9 microm diameter arteriole). This lack of flow velocity oscillations may have profound long-term effects on shear stress regulated arteriolar remodeling.

Arterioles↗

PubMed2006

Differential gene and protein expression in abluminal sprouting and intraluminal splitting forms of angiogenesis.

In adult skeletal muscle, abluminal sprouting or longitudinal splitting of capillaries can be initiated separately by muscle overload and elevated microcirculation shear stress respectively. In the present study, gene and protein expression patterns associated with the different forms of angiogenesis were examined using a targeted gene array (Superarray), validated by quantitative RT (reverse transcription)-PCR and immunoblots. Sprouting angiogenesis induced large changes in expression levels in genes associated with extracellular matrix remodelling, such as MMP-2 (matrix metalloproteinase-2), TIMP (tissue inhibitor of metalloproteinases), SPARC (secreted protein, acidic and rich in cysteine) and thrombospondin. Changes in neuropilin, midkine and restin levels, which may underpin changes in endothelial morphology, were seen during splitting angiogenesis. Up-regulation of VEGF (vascular endothelial growth factor), Flk-1, angiopoietin-2 and PECAM-1 (platelet/endothelial cell adhesion molecule-1) was seen in both forms of angiogenesis, representing a common angiogenic response of endothelial cells. In conclusion, the present study demonstrates that general angiogenic signals from growth factors can be influenced by the local microenvironment resulting in differing forms of capillary growth to produce a co-ordinated expansion of the vascular bed.

Angiogenic Proteins↗

PubMed2005

Remodeling of blood vessels: responses of diameter and wall thickness to hemodynamic and metabolic stimuli.

Vascular functions, including tissue perfusion and peripheral resistance, reflect continuous structural adaptation (remodeling) of blood vessels in response to several stimuli. Here, a theoretical model is presented that relates the structural and functional properties of microvascular networks to the adaptive responses of individual segments to hemodynamic and metabolic stimuli. All vessels are assumed to respond, according to a common set of adaptation rules, to changes in wall shear stress, circumferential wall stress, and tissue metabolic status (indicated by partial pressure of oxygen). An increase in vessel diameter with increasing wall shear stress and an increase in wall mass with increased circumferential stress are needed to ensure stable vascular adaptation. The model allows quantitative predictions of the effects of changes in systemic hemodynamic conditions or local adaptation characteristics on vessel structure and on peripheral resistance. Predicted effects of driving pressure on the ratio of wall thickness to vessel diameter are consistent with experimental observations. In addition, peripheral resistance increases by approximately 65% for an increase in driving pressure from 50 to 150 mm Hg. Peripheral resistance is predicted to be markedly increased in response to a decrease in vascular sensitivity to wall shear stress, and to be decreased in response to increased tissue metabolic demand. This theoretical approach provides a framework for integrating available information on structural remodeling in the vascular system and predicting responses to changing conditions or altered vascular reactivity, as may occur in hypertension.

Adaptation, Physiological↗

PubMed2005

Adrenomedullin treatment abolishes ileal mucosal hypoperfusion induced by Staphylococcus aureus alpha-toxin--an intravital microscopic study on an isolated rat ileum.

OBJECTIVE: Disturbances of intestinal microcirculation associated with sepsis and septic shock result in diminished mucosal oxygenation. Tissue hypoxia as well as mediator formation may lead to intestinal mucosa dysfunction. As a consequence, bacteria and their products as well as gut-derived inflammatory mediators may further perpetuate septic and inflammatory events. Adrenomedullin is produced in the mucosa of the gastrointestinal tract and has been shown to improve survival in experimental sepsis. Using pore-forming Staphylococcus aureus alpha-toxin as a potent initiator of inflammatory reactions, we tested the hypothesis that exogenously added adrenomedullin improves ileal mucosal perfusion. DESIGN: Prospective, experimental study. SETTING: University laboratory. SUBJECTS: Isolated perfused ileum from male Sprague-Dawley rats INTERVENTIONS: Adrenomedullin treatment of S. aureus alpha-toxin infused ileum. MEASUREMENT AND MAIN RESULTS: An infusion of alpha-toxin (0.05 microg/mL) induced a significant decrease of red blood cell velocity in villus terminal arterioles from 1.7 to 0.7 mm/sec assessed by intravital microscopy. This was accompanied by a significant reduction of mucosal hemoglobin oxygenation from 71.8% to 17.5% and impaired oxygen uptake. At constant bulk flow and oxygen delivery, these data indicate a redistribution of blood perfusion away from mucosa. Subsequent intervention with 0.1 microM adrenomedullin redistributed blood flow back toward the mucosa, causing an improvement of mucosal hemoglobin oxygenation and of organ oxygen uptake. CONCLUSION: These data suggest that exogenously added adrenomedullin protects ileum mucosa by diminishing alpha-toxin-induced microcirculatory disturbances. Further investigations will have to clarify the therapeutic potential of adrenomedullin in sepsis-related gut dysfunction.

Adrenomedullin↗

PubMed2004

Structural remodeling of mouse gracilis artery after chronic alteration in blood supply.

The goals of this study were to determine the time course and spatial dependence of structural diameter changes in the mouse gracilis artery after a redistribution of blood flow and to compare the observations with predictions of computational models for structural adaptation. Diameters were measured 1, 2, 7, 14, 21, 28, and 56 days after resection of one of the two blood supplies to the artery. Overall average diameter, normalized with respect to diameters in untreated vessels, increased slightly during the first 7 days, then increased more rapidly, reaching a peak around day 21, and then decreased. This transient increase in diameter was spatially nonuniform, being largest toward the point of resection. A previously developed theoretical model, in which diameter varies in response to stimuli derived from local metabolic and hemodynamic conditions, was extended to include effects of time-delayed remodeling stimuli in regions of reduced perfusion. Predictions of this model were consistent with observed diameter changes, including the transient increase in diameters near the point of resection, when a remodeling stimulus with a time delay of approximately 7 days was included. The results suggest that delayed stimuli significantly influence the dynamic characteristics of vascular remodeling resulting from reduced blood supply.

Adaptation, Physiological↗

PubMed2004

Endothelial NOS is main mediator for shear stress-dependent angiogenesis in skeletal muscle after prazosin administration.

The increase of wall shear stress in capillaries by oral administration of the alpha1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Because endothelial nitric oxide synthase (eNOS) is upregulated in response to elevated wall shear stress, we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) were given to C57BL/6 wild-type mice and eNOS-knockout mice for 14 days. The capillary-to-fiber (C/F) ratio and capillary density (CD; no. of capillaries/mm2) were determined in frozen sections from extensor digitorum longus (EDL) muscles of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles, whereas VEGF (after precipitation with heparin-agarose) and neuronal NOS (nNOS) concentrations were determined in EDL solubilizates. In EDL muscles of C57BL/6 mice treated for 14 days, the C/F ratio was 28% higher after prazosin administration and 11% higher after prazosin and L-NAME feeding, whereas the CD increased by 21 and 13%, respectively. The C/F ratio was highest after day 4 of prazosin treatment and decreased gradually to almost constant values after day 8. Prazosin administration led to elevation of eNOS expression. VEGF levels were lowest at day 4, whereas nNOS values decreased after day 8. In EDL muscles of eNOS-knockout mice, no significant changes in C/F ratio, CD, or VEGF and nNOS expression were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle, albeit other signaling molecules might partially compensate for or contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential downregulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis.

Adrenergic alpha-Antagonists↗

PubMed2004

Microviscometry reveals reduced blood viscosity and altered shear rate and shear stress profiles in microvessels after hemodilution.

We show that many salient hemodynamic flow properties, which have been difficult or impossible to assess in microvessels in vivo, can be estimated by using microviscometry and fluorescent microparticle image velocimetry in microvessels >20 microm in diameter. Radial distributions in blood viscosity, shear stress, and shear rate are obtained and used to predict axial pressure gradient, apparent viscosity, and endothelial-cell surface-layer thickness in vivo. Based solely on microparticle image velocimetry data, which are readily obtainable during the course of most intravital microscopy protocols from systemically injected particle tracers, we show that the microviscometric method consistently predicted a reduction in local and apparent blood viscosity after isovolemic hemodilution. Among its clinical applications, hemodilution is a procedure that is used to treat various pathologies that require reduction in peripheral vascular-flow resistance. Our results are directly relevant in this context because they suggest that the fractional decrease in systemic hematocrit is approximately 25-35% greater than the accompanying fractional decrease in microvascular-flow resistance in vivo. In terms of its fundamental usefulness, the microviscometric method provides a comprehensive quantitative analysis of microvascular hemodynamics that has applications in broad areas of medicine and physiology and is particularly relevant to quantitative studies of angiogenesis, tumor growth, leukocyte adhesion, vascular-flow resistance, tissue perfusion, and endothelial-cell mechanotransduction.

Blood Flow Velocity↗

PubMed2004

Effects of unfractionated heparin, low molecular weight heparin and r-hirudin on leukocyte adhesion in ischemia/reperfusion.

Activation of the coagulation cascade during myocardial ischemia and reperfusion may contribute to the post-ischemic inflammatory response, mostly via generation of thrombin. We assessed the effect of the anticoagulants unfractionated heparin (UFH), low molecular weight heparin (LMWH) and r-hirudin on leukocyte adhesion and emigration after ischemia and reperfusion in rats. The rat cremaster muscle was prepared for intravital microscopy. One hundred and twenty minutes of ischemia were followed by 90 min of reperfusion. Saline (control), UFH, LMWH or r-hirudin were given 15 min prior to reperfusion and infused for the rest of the observation period. Dosages per kilogram of body weight were (bolus, infusion): saline, 3 ml, 3 ml/h; UFH, 400 IU, 100 IU/h; LMWH, 100 IU, 3 ml/h saline; or r-hirudin, 0.3 mg, 0.15 mg/h. In collecting venules, rolling, adherent, and extravasated leukocytes were counted from recordings of the intravital microscopy. All three anticoagulants similarly attenuated post-ischemic endothelial leukocyte adhesion. In contrast, emigration of leukocytes was only attenuated by r-hirudin. The emigration efficiency of adherent leukocytes (control, 1.21) was unchanged after UFH (1.74), and LMWH (1.51) but decreased after r-hirudin treatment (0.12). The different efficacy of the three anticoagulants in affecting emigration of adherent leukocytes suggests a specific role for the direct thrombin inhibitor r-hirudin in attenuating the post-ischemic inflammatory response. This effect may contribute to the benefits of direct thrombin inhibitors seen in clinical studies after treatment for acute coronary syndromes.

Animals↗

PubMed2003

The endothelium as physiological source of properdin: role of wall shear stress.

Properdin is a positive regulator of the alternative pathway of complement activation. It can be released by peripheral blood cells but is not synthesized in the liver and the physiological source of properdin in plasma is unknown. The endothelium is an extra-hepatic source for several complement components and shear stress can modulate their expression. The aim of this study was to analyze shear stress-exposed endothelial cells (EC) as physiological source for plasma properdin. Human umbilical vein EC (HUVEC) and human cardiac microvascular EC (HCMEC) were exposed to shear stress using a cone-and-plate apparatus and properdin expression was analyzed by RT-PCR, Northern, and Western blot. mRNA for properdin is barely detectable in untreated EC but strongly induced by laminar shear stress exposure (6 dyn/cm(2); 24 h). Properdin is induced also at the protein level and is released in the extracellular compartment. Properdin up-regulation requires a shear stress of 2-3 dyn/cm(2), is not transient, and is reversible by restoration of static conditions. Turbulent flow exposure results in two times higher induction of properdin than laminar flow exposure. The ability of endothelial cells exposed to shear stress to synthesize properdin proposes the endothelium as physiological source for plasma properdin and suggests a link between flow conditions and the modulation of the alternative pathway. Furthermore, the stronger properdin induction by turbulent flow may suggest an involvement in the pathology of atherosclerosis.

Cells, Cultured↗

PubMed2003

Selective blockade of endothelial Ca2+-activated small- and intermediate-conductance K+-channels suppresses EDHF-mediated vasodilation.

1. Activation of Ca(2+)-activated K(+)-channels (K(Ca)) has been suggested to play a key role in endothelium-derived hyperpolarizing factor (EDHF)-mediated vasodilation. However, due to the low selectivity of commonly used K(Ca)-channel blockers it is still elusive which endothelial K(Ca)-subtypes mediate hyperpolarization and thus initiate EDHF-mediated vasodilation. 2. Using the non-cytochrome P450 blocking clotrimazole-derivatives, 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) and 2-(2-chlorophenyl)-2,2-diphenylacetonitrile (TRAM-39) as highly selective IK1-inhibitors, we investigated the role of the intermediate-conductance K(Ca) (rIK1) in endothelial hyperpolarization and EDHF-mediated vasodilation. 3. Expression and function of rIK1 and small-conductance K(Ca) (rSK3) were demonstrated in situ in single endothelial cells of rat carotid arteries (CA). rIK1-currents were blocked by TRAM-34 or TRAM-39, while rSK3 was blocked by apamin. In current-clamp experiments, endothelial hyperpolarization in response to acetylcholine was abolished by the combination of apamin and TRAM-34. 4. In phenylephrine-preconstricted CA, acetylcholine-induced NO and prostacyclin-independent vasodilation was almost completely blocked by ChTX, CLT, TRAM-34, or TRAM-39 in combination with the SK3-blocker apamin. Apamin, TRAM-34, and CLT alone or sulphaphenzole, a blocker of the cytochrome P450 isoform 2C9, were ineffective in blocking the EDHF-response. 5. In experiments without blocking NO and prostacyclin synthesis, the combined blockade of SK3 and IK1 reduced endothelium-dependent vasodilation. 6. In conclusion, the use of selective IK1-inhibitors together with the SK3-blocker apamin revealed that activation of both K(Ca), rIK1 and rSK3 is crucial in mediating endothelial hyperpolarization and generation of the EDHF-signal while the cytochrome P450 pathway seems to play a minor or no role in rat CA.

Animals↗

PubMed2002

Vascular endothelial growth factor is expressed in endothelial cells isolated from skeletal muscles of nitric oxide synthase knockout mice during prazosin-induced angiogenesis.

In skeletal muscles, angiogenesis can be induced by increases in wall shear stress. To identify molecules involved in the angiogenic process, a method based on the use of BS-1 lectin-coated magnetic beads was developed to isolate a cellular fraction enriched in microvascular endothelial cells which are directly exposed to wall shear stress. Using such cellular fractions from skeletal muscles of C57 mice in which angiogenesis was induced by administration with the alpha(1)-adrenergic antagonist prazosin, we found the concentration of vascular endothelial growth factor (VEGF) increased in correlation to the duration of the prazosin stimulus. In contrast, the angiopoietin-2/tie-2 system was not changed even after 4days of prazosin treatment. In neuronal nitric oxide synthase (nNOS) knockout mice, the VEGF concentration was also elevated after prazosin treatment but remained almost unchanged in endothelial nitric oxide synthase (eNOS) knockout mice. However, eNOS (and not nNOS) knockout mice expressed higher levels of VEGF under non-stimulated conditions as compared to C57 mice. These results suggest that VEGF produced in endothelial cells is involved in angiogenesis in skeletal muscles of mice responding to the administration of systemic vasodilators. NO derived from eNOS and nNOS may be an important regulator of the angiogenic response in skeletal muscles in vivo.

Adrenergic alpha-Antagonists↗

PubMed2002

Structural adaptation of microvascular networks and development of hypertension.

Blood vessels are capable of dynamic structural adaptation in which their diameters and wall thicknesses change in response to chronic changes in hemodynamic conditions. Such structural changes can have large effects on vascular resistance to blood flow. Structural responses to hemodynamic stresses, i.e., wall shear stress resulting from blood flow and circumferential wall tension resulting from transmural pressure, have been extensively documented. Generally, increased shear stress causes increases in vessel diameter, whereas increased transmural pressure causes opposite effects. Theoretical models have been developed to analyze the consequences of these responses for the behavior of microvascular networks when subjected to changes in systemic circulatory conditions. An initial increase of cardiac output is assumed to increase flow and driving pressure in parallel. According to the models, structural adaptation results in substantially increased overall network flow resistance as flow is increased, and thus amplification of the initially imposed increase in driving pressure. This behavior, resulting from adaptation of individual vessel segments to intravascular pressure, is consistent with data on the development of hypertension, which suggest that an increase in cardiac output precedes the increase in peripheral resistance that is characteristic of established hypertension. Thus, vascular sensitivity to circumferential wall stress may play a crucial role in the development of hypertension.

Adaptation, Physiological↗

PubMed2002

Information transfer in microvascular networks.

The adequate and efficient functioning of the circulatory system requires coordination of vessel diameters and of vascular responses to local and remote stimuli. Such coordination implies transfer of information about functional status and demands to all parts of the vascular system. In the peripheral circulation, blood flow must be controlled locally to accommodate spatial variations in demand. This requires information transfer from peripheral vessels to the more proximal vessels that feed and drain them. Principal mechanisms available for this information transfer are hemodynamic coupling, diffusive and convective transport of metabolites, and responses conducted along vessel walls. Current knowledge of these mechanisms is reviewed here. Theoretical models provide a framework for examining how information transfer mechanisms and vascular responses are integrated, so as to provide short-term regulation of blood flow and long-term structural adaptation of microvascular networks.

Adaptation, Physiological↗

PubMed2002

Interaction of albumin with the endothelial cell surface.

Endothelial cells (EC) are covered with cell-borne proteoglycans and glycoproteins. Blood plasma proteins (e.g., albumin) adsorb to this glycocalyx forming a complex endothelial surface layer (ESL). We determined the molecular mobility of albumin by electron spin resonance (ESR) in the presence and absence of ECs to analyze interactions with the ESL. Albumin was spin labeled with 5- or 12-4,4-dimethyloxazolidine-N-oxyl (DOXYL)-stearic acid yielding information on the mobility of the molecular surface (5-DOXYL) or the entire protein (12-DOXYL). EC cultures grown on glass coverslips were immersed in labeled albumin and placed in the temperature-regulated cavity of an ESR spectrometer. Alternatively, ECs were labeled and then exposed to native albumin. At 37 degrees C, rotational correlation times determined by modified saturation transfer ESR (ST-ESR) were 26 and 48 ns for 5-DOXYL- and 12-DOXYL-labeled albumin, respectively. Presence of ECs increased rotational correlation time values for 5-DOXYL-stearic acid to 37 ns but not for 12-DOXYL-stearic acid. Albumin was able to completely take up the label from labeled EC within 2 min. The present study shows that modified ST-ESR can be used to determine the mobility of biological macromolecules interacting with cellular surfaces. Reduction in albumin surface mobility in the presence of EC at unchanged mobility of protein proper and fast removal of labeled fatty acids from EC membranes indicate rapid transient interactions between albumin surface and ESL but no rigid incorporation of albumin into a macromolecular network that would interfere with its transport function for poorly water-soluble substances.

Cell Membrane↗

PubMed2002

Angioadaptation: keeping the vascular system in shape.

The development and maintenance of the vascular system requires not only the formation of new vessels (vasculogenesis, angiogenesis) but also the continuous adjustment of vessel and network structures in response to functional needs. This "angioadaptation" depends on the interplay of vascular responses to growth factors, to the metabolic status of the tissue, and to hemodynamic forces exerted by the flowing blood.

Adaptation, Physiological↗

PubMed2001

Impaired function of endothelial pressure-activated cation channel in salt-sensitive genetic hypertension.

Mechanosensitive ion channels have been suggested to act as endothelial mechanosensors for hemodynamic forces. The present study tested the hypothesis that the pressure-activated cation channel (PAC), a novel type of endothelial mechanosensitive ion channel, is involved in salt sensitivity in the Sabra rat model of hypertension. Groups of Sabra salt-sensitive (SBH/y) and salt-resistant (SBN/y) rats were loaded with deoxycorticosterone-acetate (DOCA)-salt for 8 wk or were fed a regular diet. Single channel function of PAC in SBH/y and SBN/y rats was investigated in intact endothelium of mesenteric artery using the patch-clamp technique. After DOCA-salt treatment, the SBH/y rats showed a full hypertensive response, whereas SBN/y rats were normotensive. Rats of both strains that received a regular diet were normotensive. In endothelium of both Sabra rats, Ca(2+) permeable PAC that was activated by positive pipette pressures was identified. Apparent PAC density (percentage of patches with PAC activity) was reduced in hypertensive SBH/y rats that were loaded with DOCA-salt compared with salt-loaded normotensive SBN/y rats (6 +/- 2% versus 24 +/- 8%, respectively; P < 0.05). In normotensive SBH/y and SBN/y rats that received a regular diet, PAC density was not altered. Mechanosensitivity and unitary conductance of endothelial PAC were similar in both strains under a regular diet as well as salt loading with DOCA-salt. In conclusion, the decreased density of PAC in mesenteric endothelium from hypertensive SBH/y rats indicates an impaired ion channel regulation. The defective PAC function presumably leads to an impaired mechanosensitive Ca(2+) entry and might contribute to endothelial dysfunction and high BP in this type of salt-sensitive genetic hypertension.

Animals↗

PubMedDate not supplied

Changes in capillary shear stress in skeletal muscles exposed to long-term activity: role of nitric oxide.

OBJECTIVE: The purpose of this study was to establish whether suppression of angiogenesis by nitric oxide synthase (NOS) inhibition in skeletal muscles exposed to long-term activity can be explained by changes in capillary shear stress linked to the lack of nitric oxide production. METHODS: Capillary shear stress was calculated from diameters (d) and red blood cell velocities (V(rbc)) measured at rest and after acute contractions in epi-illuminated extensor digitorum longus muscles of control rats and those in which ankle flexors had been stimulated via implanted electrodes (10 Hz, 8 h x day(-1)) for 2 or 7 days without and with inhibition of nitric oxide synthase activity by N(omega)-nitro-L-arginine (L-NNA, 3-4 mg x day(-1) in drinking water). RESULTS: Neither chronic electrical stimulation nor L-NNA treatment altered capillary diameters. Capillary V(rbc) and shear stress (SS) were doubled in muscles after 2 days stimulation (298 +/- 22 microm x s(-1) and 11.4 +/- 1.0 dyne x cm(-2), respectively, p < .005) compared to controls (148 +/- 18 microm x s(-1) and 5.6 +/- 0.8 dyne x cm(-2)) but normalized after 7 days (153 +/- 27 microm x s(-1) and 6.2 +/- 1.0 dyne x cm(-2)), when the capillary bed is known to be enlarged. L-NNA, which increased blood pressure in all treated animals, abolished the increase in capillary SS after 2 days stimulation and decreased SS after 7 days. CONCLUSIONS: These data support a role for NO in the early elevation of capillary shear stress that initiates angiogenesis in stimulated muscles, likely via modulation of upstream vascular resistance, and could explain the lack of capillary growth in stimulated muscles when nitric oxide generation is suppressed.

Animals↗