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  • American Physiological Society  (9)
  • 2010-2014  (9)
  • 1
    Online Resource
    Online Resource
    Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Cell Physiology Vol. 303, No. 10 ( 2012-11-15), p. C1090-C1103
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 303, No. 10 ( 2012-11-15), p. C1090-C1103
    Abstract: Chronic hypoxia increases vascular endothelial growth factor (VEGF) and thereby promotes angiogenesis. The present study explores the hypothesis that hypoxic increases in VEGF also remodel artery wall structure and contractility through phenotypic transformation of smooth muscle. Pregnant and nonpregnant ewes were maintained at sea level (normoxia) or 3,820 m (hypoxia) for the final 110 days of gestation. Common carotid arteries harvested from term fetal lambs and nonpregnant adults were denuded of endothelium and studied in vitro. Stretch-dependent contractile stresses were 32 and 77% of normoxic values in hypoxic fetal and adult arteries. Hypoxic hypocontractility was coupled with increased abundance of nonmuscle myosin heavy chain (NM-MHC) in fetal (+37%) and adult (+119%) arteries. Conversely, hypoxia decreased smooth muscle MHC (SM-MHC) abundance by 40% in fetal arteries but increased it 123% in adult arteries. Hypoxia decreased colocalization of NM-MHC with smooth muscle α-actin (SM-αA) in fetal arteries and decreased colocalization of SM-MHC with SM-αA in adult arteries. Organ culture with physiological concentrations (3 ng/ml) of VEGF-A 165 similarly depressed stretch-dependent stresses to 37 and 49% of control fetal and adult values. The VEGF receptor antagonist vatalanib ablated VEGF's effects in adult but not fetal arteries, suggesting age-dependent VEGF receptor signaling. VEGF replicated hypoxic decreases in colocalization of NM-MHC with SM-αA in fetal arteries and decreases in colocalization of SM-MHC with SM-αA in adult arteries. These results suggest that hypoxic increases in VEGF not only promote angiogenesis but may also help mediate hypoxic arterial remodeling through age-dependent changes in smooth muscle phenotype and contractility.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00408.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 2
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    Online Resource
    Substrate stiffening promotes endothelial monolayer disruption through enhanced physical forces
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Cell Physiology Vol. 300, No. 1 ( 2011-01), p. C146-C154
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 300, No. 1 ( 2011-01), p. C146-C154
    Abstract: A hallmark of many, sometimes life-threatening, inflammatory diseases and disorders is vascular leakage. The extent and severity of vascular leakage is broadly mediated by the integrity of the endothelial cell (EC) monolayer, which is in turn governed by three major interactions: cell-cell and cell-substrate contacts, soluble mediators, and biomechanical forces. A potentially critical but essentially uninvestigated component mediating these interactions is the stiffness of the substrate to which the endothelial monolayer is adherent. Accordingly, we investigated the extent to which substrate stiffening influences endothelial monolayer disruption and the role of cell-cell and cell-substrate contacts, soluble mediators, and physical forces in that process. Traction force microscopy showed that forces between cell and cell and between cell and substrate were greater on stiffer substrates. On stiffer substrates, these forces were substantially enhanced by a hyperpermeability stimulus (thrombin, 1 U/ml), and gaps formed between cells. On softer substrates, by contrast, these forces were increased far less by thrombin, and gaps did not form between cells. This stiffness-dependent force enhancement was associated with increased Rho kinase activity, whereas inhibition of Rho kinase attenuated baseline forces and lessened thrombin-induced inter-EC gap formation. Our findings demonstrate a central role of physical forces in EC gap formation and highlight a novel physiological mechanism. Integrity of the endothelial monolayer is governed by its physical microenvironment, which in normal circumstances is compliant but during pathology becomes stiffer.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00195.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    Fluidization, resolidification, and reorientation of the endothelial cell in response to slow tidal stretches
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Cell Physiology Vol. 303, No. 4 ( 2012-08-15), p. C368-C375
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 303, No. 4 ( 2012-08-15), p. C368-C375
    Abstract: Mechanical stretch plays an important role in regulating shape and orientation of the vascular endothelial cell. This morphological response to stretch is basic to angiogenesis, neovascularization, and vascular homeostasis, but mechanism remains unclear. To elucidate mechanisms, we used cell mapping rheometry to measure traction forces in primary human umbilical vein endothelial cells subjected to periodic uniaxial stretches. Onset of periodic stretch of 10% strain amplitude caused a fluidization response typified by attenuation of traction forces almost to zero. As periodic stretch continued, the prompt fluidization response was followed by a slow resolidification response typified by recovery of the traction forces, but now aligned along the axis perpendicular to the imposed stretch. Reorientation of the cell body lagged reorientation of the traction forces, however. Together, these observations demonstrate that cellular reorientation in response to periodic stretch is preceded by traction attenuation by means of cytoskeletal fluidization and subsequent traction recovery transverse to the stretch direction by means of cytoskeletal resolidification.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00074.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Cell Physiology Vol. 301, No. 3 ( 2011-09), p. C653-C666
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 301, No. 3 ( 2011-09), p. C653-C666
    Abstract: The present study explores the hypothesis that arterial smooth muscle cells are organized into layers with similar phenotypic characteristics that vary with the relative position between the lumen and the adventitia due to transmural gradients in vasotrophic factors. A corollary hypothesis is that vascular endothelial growth factor (VEGF) is a factor that helps establish transmural variations in smooth muscle phenotype. Organ culture of endothelium-denuded ovine carotid arteries with 3 ng/ml VEGF-A 165 for 24 h differentially and significantly influenced potassium-induced (55% increase) and stretch-induced (36% decrease) stress-strain relations in adult ( n = 18) but not term fetal ( n = 21) arteries, suggesting that smooth muscle reactivity to VEGF is acquired during postnatal maturation. Because inclusion of fetal bovine serum significantly inhibited all contractile effects of VEGF (adult: n = 11; fetus: n = 11), it was excluded in all cultures. When assessed in relation to the distance between the lumen and the adventitia in immunohistochemically stained coronal artery sections, expression of smooth muscle α-actin (SMαA), myosin light chain kinase (MLCK), and 20-kDa regulatory myosin light chain exhibited distinct protein-dependent and age-dependent gradients across the artery wall. VEGF depressed regional SMαA abundance up to 15% in adult ( n = 6) but not in fetal ( n = 6) arteries, increased regional MLCK abundance up to 140% in fetal ( n = 8) but not in adult ( n = 10) arteries, and increased regional MLC 20 abundance up to 28% in fetal arteries ( n = 7) but decreased it by 17% in adult arteries ( n = 9). Measurements of mRNA levels verified that VEGF receptor transcripts for both Flt-1 and kinase insert domain receptor (KDR) were expressed in both fetal and adult arteries. Overall, the present data support the unique hypothesis that smooth muscle cells are organized into lamina of similar phenotype with characteristics that depend on the relative position between the lumen and the adventitia and involve the direct effects of growth factors such as VEGF, which acts independently of the vascular endothelium in an age-dependent manner.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00413.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Upper airway collapsibility and patterns of flow limitation at constant end-expiratory lung volume
    American Physiological Society ; 2012
    In:  Journal of Applied Physiology Vol. 113, No. 5 ( 2012-09-01), p. 691-699
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 113, No. 5 ( 2012-09-01), p. 691-699
    Abstract: The passive pharyngeal critical closing pressure (Pcrit) is measured using a series of pressure drops. However, pressure drops also lower end-expiratory lung volume (EELV), which independently affects Pcrit. We describe a technique to measure Pcrit at a constant EELV. Continuous positive airway pressure (CPAP)-treated obstructive sleep apnea (OSA) patients and controls were instrumented with an epiglottic catheter, magnetometers (to measure change in EELV), and nasal mask/pneumotachograph and slept supine on nasal CPAP. Pcrit was measured in standard fashion and using our novel “biphasic technique” in which expiratory pressure only was lowered for 1 min before the inspiratory pressure was dropped; this allowed EELV to decrease to the drop level before performing the pressure drop. Seven OSA and three controls were studied. The biphasic technique successfully lowered EELV before the inspiratory pressure drop. Pcrit was similar between the standard and biphasic techniques (−0.4 ± 2.6 vs. −0.6 ± 2.3 cmH 2 O, respectively, P = 0.84). Interestingly, we noted three different patterns of flow limitation: 1) classic Starling resistor type: flow fixed and independent of downstream pressure; 2) negative effort dependence within breaths: substantial decrease in flow, sometimes with complete collapse, as downstream pressure decreased; and 3) and negative effort dependence across breaths: progressive reductions in peak flow as respiratory effort on successive breaths increased. Overall, EELV changes do not influence standard passive Pcrit measurements if breaths 3–5 of pressure drops are used. These results also highlight the importance of inspiratory collapse in OSA pathogenesis. The cause of negative effort dependence within and across breaths is not known and requires further study.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00091.2012
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 6
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    Online Resource
    Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Cell Physiology Vol. 304, No. 7 ( 2013-04-01), p. C656-C665
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 304, No. 7 ( 2013-04-01), p. C656-C665
    Abstract: Recent studies suggest that vascular endothelial growth factor (VEGF) can modulate smooth muscle phenotype and, consequently, the composition and function of arteries upstream from the microcirculation, where angiogenesis occurs. Given that hypoxia potently induces VEGF, the present study explores the hypothesis that, in fetal arteries, VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins. Pregnant ewes were acclimatized at sea level or at altitude (3,820 m) for the final 110 days of gestation. Endothelium-denuded carotid arteries from full-term fetuses were used fresh or after 24 h of organ culture in a physiological concentration (3 ng/ml) of VEGF. After 110 days, hypoxia had no effect on VEGF abundance but markedly increased abundance of the Flk-1 (171%) and Flt-1 (786%) VEGF receptors. Hypoxia had no effect on smooth muscle α-actin (SMαA), decreased myosin light chain (MLC) kinase (MLCK), and increased 20-kDa regulatory MLC (MLC 20 ) abundances. Hypoxia also increased MLCK-SMαA, MLC 20 -SMαA, and MLCK-MLC 20 colocalization. Compared with hypoxia, organ culture with VEGF produced the same pattern of changes in contractile protein abundance and colocalization. Effects of VEGF on colocalization were blocked by the VEGF receptor antagonists vatalanib (240 nM) and dasatinib (6.3 nM). Thus, through increases in VEGF receptor density, hypoxia can recruit VEGF to help mediate remodeling of fetal arteries upstream from the microcirculation. The results support the hypothesis that VEGF contributes to hypoxic vascular remodeling through changes in abundance, organization, and function of contractile proteins.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00110.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 7
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    Online Resource
    Model-based characterization of ventilatory stability using spontaneous breathing
    American Physiological Society ; 2011
    In:  Journal of Applied Physiology Vol. 111, No. 1 ( 2011-07), p. 55-67
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 111, No. 1 ( 2011-07), p. 55-67
    Abstract: Cyclic ventilatory instabilities are widely attributed to an increase in the sensitivity or loop gain of the chemoreflex feedback loop controlling ventilation. A major limitation in the conventional characterization of this feedback loop is the need for labor-intensive methodologies. To overcome this limitation, we developed a method based on trivariate autoregressive modeling using ventilation, end-tidal Pco 2 and Po 2 ; this method provides for estimation of the overall “loop gain” of the respiratory control system and its components, chemoreflex gain and plant gain. Our method was applied to recordings of spontaneous breathing in 15 anesthetized, tracheostomized, newborn lambs before and after administration of domperidone (a dopamine D 2 -receptor antagonist that increases carotid body sensitivity). We quantified the known increase in hypoxic ventilatory sensitivity in response to domperidone; controller gain for O 2 increased from 0.06 (0.03, 0.09) l·min −1 ·mmHg −1 to 0.09 (0.08, 0.13) l·min −1 ·mmHg −1 ; median (interquartile-range). We also report that domperidone increased the loop gain of the control system more than twofold [0.14 (0.12, 0.22) to 0.40 (0.15, 0.57)]. We observed no significant changes in CO 2 controller gain, or plant gains for O 2 and CO 2 . Furthermore, our estimate of the cycle duration of periodic breathing compared favorably with that observed experimentally [measured: 7.5 (7.2, 9.1) vs. predicted: 7.9 (7.0, 9.2) breaths]. Our results demonstrate that model-based analysis of spontaneous breathing can 1) characterize the dynamics of the respiratory control system, and 2) provide a simple tool for elucidating an individual's propensity for ventilatory instability, in turn allowing potential therapies to be directed at the underlying mechanisms.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.01358.2010
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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  • 8
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    Online Resource
    Mapping the cytoskeletal prestress
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Cell Physiology Vol. 298, No. 5 ( 2010-05), p. C1245-C1252
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 298, No. 5 ( 2010-05), p. C1245-C1252
    Abstract: Cell mechanical properties on a whole cell basis have been widely studied, whereas local intracellular variations have been less well characterized and are poorly understood. To fill this gap, here we provide detailed intracellular maps of regional cytoskeleton (CSK) stiffness, loss tangent, and rate of structural rearrangements, as well as their relationships to the underlying regional F-actin density and the local cytoskeletal prestress. In the human airway smooth muscle cell, we used micropatterning to minimize geometric variation. We measured the local cell stiffness and loss tangent with optical magnetic twisting cytometry and the local rate of CSK remodeling with spontaneous displacements of a CSK-bound bead. We also measured traction distributions with traction microscopy and cell geometry with atomic force microscopy. On the basis of these experimental observations, we used finite element methods to map for the first time the regional distribution of intracellular prestress. Compared with the cell center or edges, cell corners were systematically stiffer and more fluidlike and supported higher traction forces, and at the same time had slower remodeling dynamics. Local remodeling dynamics had a close inverse relationship with local cell stiffness. The principal finding, however, is that systematic regional variations of CSK stiffness correlated only poorly with regional F-actin density but strongly and linearly with the regional prestress. Taken together, these findings in the intact cell comprise the most comprehensive characterization to date of regional variations of cytoskeletal mechanical properties and their determinants.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00417.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477334-X
    SSG: 12
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  • 9
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    Online Resource
    The classical Starling resistor model often does not predict inspiratory airflow patterns in the human upper airway
    American Physiological Society ; 2014
    In:  Journal of Applied Physiology Vol. 116, No. 8 ( 2014-04-15), p. 1105-1112
    Details
    In: Journal of Applied Physiology, American Physiological Society, Vol. 116, No. 8 ( 2014-04-15), p. 1105-1112
    Abstract: The upper airway is often modeled as a classical Starling resistor, featuring a constant inspiratory airflow, or plateau, over a range of downstream pressures. However, airflow tracings from clinical sleep studies often show an initial peak before the plateau. To conform to the Starling model, the initial peak must be of small magnitude or dismissed as a transient. We developed a method to simulate fast or slow inspirations through the human upper airway, to test the hypothesis that this initial peak is a transient. Eight subjects [4 obstructive sleep apnea (OSA), 4 controls] slept in an “iron lung” and wore a nasal mask connected to a continuous/bilevel positive airway pressure machine. Downstream pressure was measured using an epiglottic catheter. During non-rapid eye movement (NREM) sleep, subjects were hyperventilated to produce a central apnea, then extrathoracic pressure was decreased slowly (∼2–4 s) or abruptly ( 〈 0.5 s) to lower downstream pressure and create inspiratory airflow. Pressure-flow curves were constructed for flow-limited breaths, and slow vs. fast reductions in downstream pressure were compared. All subjects exhibited an initial peak and then a decrease in flow with more negative pressures, demonstrating negative effort dependence (NED). The rate of change in downstream pressure did not affect the peak to plateau airflow ratio: %NED 22 ± 13% (slow) vs. 20 ± 5% (fast), P = not significant. We conclude that the initial peak in inspiratory airflow is not a transient but rather a distinct mechanical property of the upper airway. In contrast to the classical Starling resistor model, the upper airway exhibits marked NED in some subjects.
    Type of Medium: Online Resource
    ISSN: 8750-7587 , 1522-1601
    URL: Article
    DOI: 10.1152/japplphysiol.00853.2013
    RVK:
    WA 15000
    RVK:
    XA 52094
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1404365-8
    SSG: 12
    SSG: 31
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