TGF β‐1 mediated increase in Nox‐4 expression enhances hypoxic pulmonary vasoconstriction in bovine pulmonary arteries

Previous studies indicated that acute hypoxia increased intracellular Ca2+ concentration ([Ca2+]i), Ca2+ influx, and capacitative Ca2+ entry (CCE) through store-operated Ca2+ channels (SOCC) in smooth muscle cells from distal pulmonary arteries (PASMC), which are thought to be a major locus of hypoxic pulmonary vasoconstriction (HPV). Moreover, these effects were blocked by Ca2+-free conditions and antagonists of SOCC and nonselective cation channels (NSCC). To test the hypothesis that in vivo HPV requires CCE, we measured the effects of SOCC/NSCC antagonists (SKF-96365, NiCl2, and LaCl3) on pulmonary arterial pressor responses to 2% O2 and high-KCl concentrations in isolated rat lungs. At concentrations that blocked CCE and [Ca2+]i responses to hypoxia in PASMC, SKF-96365 and NiCl2 prevented and reversed HPV but did not alter pressor responses to KCl. At 10 μM, LaCl3 had similar effects, but higher concentrations (30 and 100 μM) caused vasoconstriction during normoxia and potentiated HPV, indicating actions other than SOCC blockade. Ca2+-free perfusate and the voltage-operated Ca2+ channel (VOCC) antagonist nifedipine were potent inhibitors of pressor responses to both hypoxia and KCl. We conclude that HPV required influx of Ca2+ through both SOCC and VOCC. This dual requirement and virtual abolition of HPV by either SOCC or VOCC antagonists suggests that neither channel provided enough Ca2+ on its own to trigger PASMC contraction and/or that during hypoxia, SOCC-dependent depolarization caused secondary activation of VOCC.

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Abstract 276: Heme Oxygenase-1 Induction Modulates Hypoxic Pulmonary Vasoconstriction

Circulation ◽

10.1161/circ.116.suppl_16.ii_35-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Mansoor Ahmad ◽

Nader G Abraham ◽

Michael S Wolin

Keyword(s):

Organ Culture ◽

Heme Oxygenase ◽

Cobalt Chloride ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Heme Oxygenase 1 ◽

Force Development ◽

Pulmonary Vasoconstriction ◽

Copper Chelator ◽

Relaxing Effect

Endothelium removed Bovine pulmonary arteries (BPA) contract to hypoxia through a mechanism potentially involving lowering of superoxide-derived hydrogen peroxide and removing its basal relaxing effect. Induction of heme oxygenase-1 (HO-1) in BPA by 24 hr organ culture with 0.1mM cobalt chloride was accompanied by a decrease in 5μM lucigenin-detectable superoxide and an increase in horseradish peroxidase-luminol detectable peroxide levels. Force development to 20mM KCl in BPA was not affected by HO-1, but hypoxic pulmonary vasoconstriction (HPV) was significantly reduced. Organ culture with a HO-1 inhibitor (10μM chromium mesoporphyrin) reversed the effects of HO-1 on HPV and peroxide. Pretreatment of BPA with a copper chelator 10mM diethyldithiocarbamate (DETCA) to inactivate Cu,Zn-SOD, prevented the conversion of superoxide to peroxide, and attenuated HPV. DETCA treatment increased superoxide and decreased peroxide to similar levels in control and HO-1 induced BPA. Peroxide scavenging with 0.1mM ebselen increased force development to 20mM KCl and partially reversed the decrease in HPV seen on induction of HO-1. Thus HO-1 induction in BPA causes an increase in superoxide scavenging by Cu,Zn-SOD resulting in increased levels of peroxide, leading to an attenuation of HPV. The generation of superoxide in BPA is not affected by HO-1 induction as DETCA treated control and HO-1 BPA show similar levels of superoxide. Thus, HO-1 induction appears to attenuate HPV in BPA by increasing the conversion of superoxide to peroxide, leading to peroxide levels which may not be adequately lowered by hypoxia.

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Hypoxic induction of Ca2+-dependent action potentials in small pulmonary arteries of the cat

Journal of Applied Physiology ◽

10.1152/jappl.1985.59.5.1389 ◽

1985 ◽

Vol 59 (5) ◽

pp. 1389-1393 ◽

Cited By ~ 73

Author(s):

D. R. Harder ◽

J. A. Madden ◽

C. Dawson

Keyword(s):

Action Potentials ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Input Resistance ◽

Potential Generation ◽

Applied Current ◽

Pulmonary Vasoconstriction ◽

Ionic Conductances ◽

The Relationship ◽

K Permeability

Small pulmonary arteries (less than 300 micron) from cats were mounted in myographs to record mechanical and electrical responses to hypoxia. When these preparations were exposed to a PO2 of 30–50 Torr after equilibration at 300 Torr they consistently developed active force, which increased or decreased in amplitude as [Ca2+] was raised or lowered, respectively, and was blocked on addition of verapamil. Intracellular electrical recording with glass microelectrodes demonstrated membrane depolarization and action potential generation when PO2 was lowered. Steady-state voltage vs. applied current curves obtained before and during hypoxia showed a significant reduction in input resistance. The relationship between membrane potential and extracellular K+ was not different during hypoxia compared with control, suggesting that there were not marked changes in K+ permeability under this condition. In the presence of verapamil to block Ca2+ inward current the hypoxia-induced action potentials were abolished concomitant with partial membrane repolarization. The results of these studies suggest that in certain isolated pulmonary arteries hypoxia induces contraction by a mechanism involving an increased Ca2+ conductance. These data suggest that the sensor involved in hypoxic pulmonary vasoconstriction may lie within the vessel wall and somehow mediates changes in smooth muscle ionic conductances.

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Development of the pulmonary vasculature in newborn lambs: structure-function relationships

Journal of Applied Physiology ◽

10.1152/jappl.1991.70.3.1255 ◽

1991 ◽

Vol 70 (3) ◽

pp. 1255-1264 ◽

Cited By ~ 18

Author(s):

R. P. Michel ◽

J. B. Gordon ◽

K. Chu

Keyword(s):

Light Microscopy ◽

Hypoxic Pulmonary Vasoconstriction ◽

Venous Pressure ◽

Pulmonary Arteries ◽

Muscle Thickness ◽

Pulmonary Vasculature ◽

Pressure Gradients ◽

Middle Segment ◽

Pulmonary Vasoconstriction ◽

Quantitative Light Microscopy

Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy, we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h, 2-4 days, 2 wk, and 1 mo. At the same ages, lungs were isolated and perfused in situ and, after cyclooxygenase blockade with indomethacin, total, arterial (delta Pa), middle (delta Pm), and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia, delta Pa and delta Pm fell significantly between 2-4 days and 2 wk, whereas during hypoxia, only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1,000 microns diam) decreased, and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance, because only arterial and middle segment resistance fell, 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction, because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia, and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1,000-microns-diam arteries.

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Responses of isolated guinea pig pulmonary venules to hypoxia and anoxia

Journal of Applied Physiology ◽

10.1152/jappl.1989.67.5.2147 ◽

1989 ◽

Vol 67 (5) ◽

pp. 2147-2153 ◽

Cited By ~ 8

Author(s):

W. R. Tracey ◽

J. T. Hamilton ◽

I. D. Craig ◽

N. A. Paterson

Keyword(s):

Guinea Pig ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Major Site ◽

Sustained Contraction ◽

Pulmonary Vasoconstriction ◽

Ph Dependent

Because small pulmonary arteries are believed to be the major site of hypoxic pulmonary vasoconstriction (HPV), pulmonary venular responses to hypoxia have received little attention. Therefore the responses of isolated guinea pig pulmonary venules to hypoxia (bath PO2, 25 Torr) and anoxia (bath PO2, 0 Torr) were characterized. Pulmonary venules [effective lumen radius (ELR), 116 +/- 2 microns] with an adherent layer of parenchyma responded to hypoxia and anoxia with a graded sustained contraction (hypoxia, 0.03 +/- 0.01; anoxia, 0.26 +/- 0.03 mN/mm), whereas paired femoral venules (ELR, 184 +/- 7 microns) contracted to anoxia only (0.05 +/- 0.02 mN/mm). Repeated challenges with hypoxia and anoxia continued to elicit sustained pulmonary venular contractions; femoral venule contractions to anoxia were not repeatable. Hypoxia- and anoxia-induced pulmonary venular contractions were calcium and pH dependent. Dissection of the parenchyma from pulmonary venules did not alter contractions to decreased PO2. Anoxic contractions of pulmonary venules were variably reduced by replacement of the bath fluid; however, the release of a contractile mediator(s) from pulmonary venules during hypoxia or anoxia was not demonstrated. Pulmonary venular responses to hypoxia and anoxia are similar to those induced by hypoxia in vivo, and results obtained from this model may be useful in predicting mechanisms of HPV.

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Nox‐4 siRNA Causes Attenuation of Hypoxic Pulmonary Vasoconstriction in Bovine Pulmonary Arteries

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.1002.8 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Mansoor Ahmad ◽

Melissa R Kelly ◽

Sharath Kandhi ◽

Xiangmin Zhao ◽

Michael S Wolin

Keyword(s):

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Pulmonary Vasoconstriction

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Hypoxic pulmonary vasoconstriction

Essays in Biochemistry ◽

10.1042/bse0430061 ◽

2007 ◽

Vol 43 ◽

pp. 61-76 ◽

Cited By ~ 8

Author(s):

A. Mark Evans

Keyword(s):

Smooth Muscle ◽

Cell Activation ◽

Calcium Release ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Right Heart Failure ◽

Cell Types ◽

Pulmonary Vasoconstriction ◽

Alveolar Hypoxia ◽

Different Cell Types

HPV (hypoxic pulmonary vasoconstriction) is the critical and distinguishing characteristic of the arteries that feed the lung. In marked contrast, systemic arteries dilate in response to hypoxia to meet the metabolic demands of the tissues they supply. Physiologically, HPV contributes to ventilation–perfusion matching in the lung by diverting blood flow to oxygen-rich areas. However, when alveolar hypoxia is global, as in diseases such as emphysema and cystic fibrosis, HPV leads to HPH (hypoxic pulmonary hypertension) and right heart failure. HPV is driven by the intrinsic response to hypoxia of two different cell types, namely the pulmonary arterial smooth muscle and endothelial cells. These are representatives of a group of specialized cells, commonly referred to as oxygen-sensing cells, which are defined by their acute sensitivity to relatively small changes in PO2 and have evolved to monitor oxygen supply and alter respiratory and circulatory function, as well as the capacity of the blood to transport oxygen. Upon exposure to hypoxia, mitochondrial oxidative phosphorylation is inhibited in all such cells and this, in part, mediates cell activation. In the case of pulmonary arteries, constriction is triggered via: (i) calcium release from the smooth muscle sarcoplasmic reticulum and consequent store-depletion-activated calcium entry into the smooth muscle cells and, (ii) the modulation of transmitter release from the pulmonary artery endothelium, which leads to further constriction of the smooth muscle by increasing the sensitivity of the contractile apparatus to calcium.

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Hypoxic pulmonary vasoconstriction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00733.2004 ◽

2005 ◽

Vol 98 (1) ◽

pp. 390-403 ◽

Cited By ~ 303

Author(s):

Rohit Moudgil ◽

Evangelos D. Michelakis ◽

Stephen L. Archer

Keyword(s):

Electron Transport ◽

Electron Transport Chain ◽

Hypoxic Pulmonary Vasoconstriction ◽

Ductus Arteriosus ◽

Pulmonary Arteries ◽

Chain Complex ◽

Adenosine Diphosphate ◽

Voltage Gated ◽

Pulmonary Vasoconstriction ◽

Transport Chain

Humans encounter hypoxia throughout their lives. This occurs by destiny in utero, through disease, and by desire, in our quest for altitude. Hypoxic pulmonary vasoconstriction (HPV) is a widely conserved, homeostatic, vasomotor response of resistance pulmonary arteries to alveolar hypoxia. HPV mediates ventilation-perfusion matching and, by reducing shunt fraction, optimizes systemic Po2. HPV is intrinsic to the lung, and, although modulated by the endothelium, the core mechanism is in the smooth muscle cell (SMC). The Redox Theory for the mechanism of HPV proposes the coordinated action of a redox sensor (the proximal mitochondrial electron transport chain) that generates a diffusible mediator [a reactive O2 species (ROS)] that regulates an effector protein [voltage-gated potassium (Kv) and calcium channels]. A similar mechanism for regulating O2 uptake/distribution is partially recapitulated in simpler organisms and in the other specialized mammalian O2-sensitive tissues, including the carotid body and ductus arteriosus. Inhibition of O2-sensitive Kv channels, particularly Kv1.5 and Kv2.1, depolarizes pulmonary artery SMCs, activating voltage-gated Ca2+ channels and causing Ca2+ influx and vasoconstriction. Downstream of this pathway, there is important regulation of the contractile apparatus' sensitivity to calcium by rho kinase. Controversy remains as to whether hypoxia decreases or increases ROS and which electron transport chain complex generates the ROS (I and/or III). Possible roles for cyclic adenosine diphosphate ribose and an unidentified endothelial constricting factor are also proposed by some groups. Modulation of HPV has therapeutic relevance to cor pulmonale, high-altitude pulmonary edema, and sleep apnea. HPV is clinically exploited in single-lung anesthesia, and its mechanisms intersect with those of pulmonary arterial hypertension.

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Videomorphometric Analysis of Hypoxic Pulmonary Vasoconstriction of Intra-pulmonary Arteries Using Murine Precision Cut Lung Slices

Journal of Visualized Experiments ◽

10.3791/50970 ◽

2014 ◽

Cited By ~ 5

Author(s):

Renate Paddenberg ◽

Petra Mermer ◽

Anna Goldenberg ◽

Wolfgang Kummer

Keyword(s):

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Pulmonary Vasoconstriction ◽

Precision Cut Lung Slices

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beta-Adrenergic mechanisms attenuated hypoxic pulmonary vasoconstriction during systemic hypoxia in cats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.5.h1777 ◽

1994 ◽

Vol 266 (5) ◽

pp. H1777-H1785 ◽

Cited By ~ 8

Author(s):

M. Shirai ◽

T. Shindo ◽

I. Ninomiya

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Hypoxic Pulmonary Vasoconstriction ◽

Pulmonary Arteries ◽

Internal Diameter ◽

Television System ◽

Autonomic Nervous ◽

Pulmonary Vasoconstriction ◽

Alveolar Hypoxia

In this study, we examined how locally mediated hypoxic pulmonary vasoconstriction is modulated by autonomic nervous system activation during global alveolar hypoxia (GAH) accompanied by systemic hypoxemia. Using an X-ray television system on the in vivo cat lung, we measured changes in the internal diameter (ID) during GAH and regional alveolar hypoxia (RAH) without systemic hypoxemia in identical small pulmonary arteries and veins (100-600 microns ID). We also analyzed the effects of the autonomic nervous system blockade on the hypoxic ID changes. During GAH the ID of the arteries reduced by 5 +/- 1 and 3 +/- 1% with 10 and 5% O2 inhalations, respectively, whereas during RAH the arterial ID reduced by 12 +/- 1 and 18 +/- 1% with 10 and 5% O2 inhalations, respectively. The magnitude of the ID reduction was significantly smaller during GAH than during RAH. After pretreatment with propranolol, however, GAH induced large ID reductions (16 +/- 1 and 23 +/- 1% with 10 and 5% O2 inhalations) with patterns very similar to those seen during RAH. Phentolamine and atropine had no effect on the response during GAH. The ID reductions during RAH, on the other hand, were unaffected by all the blockers. The results indicate that, in the cat, alveolar hypoxia per se acts locally to constrict the small pulmonary vessels and that the hypoxic vasoconstriction is attenuated by a beta-receptor-mediated vasodilator effect during GAH with systemic hypoxemia. In addition, we found that, after adrenalectomy plus ganglion blockade with hexamethonium bromide, the GAH-induced ID reduction with 5% O2 inhalation was enhanced from 3 to 19%.(ABSTRACT TRUNCATED AT 250 WORDS)

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