ID: 59: ROLE OF ENDOTHELIAL HYPOXIA–INDUCIBLE FACTORS IN HYPOXIA-INDUCED PULMONARY VASOCONSTRICITON

2016 ◽  
Vol 64 (4) ◽  
pp. 974.2-975
Author(s):  
Y Gu ◽  
H Tang ◽  
JG Garcia ◽  
JX Yuan ◽  
DR Fraidenburg ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Conditional Knockout ◽  
Induced Response ◽  
Hypoxia Inducible Factors ◽  
Pulmonary Vasoconstriction ◽  
High K ◽  
Pulmonary Arterial

RationalPulmonary arterial hypertension (PAH) is a rare but progressive and fatal disease caused by functional and structural changes in the pulmonary vasculature, which lead to an increase in pulmonary vascular resistance (PVR). Persistent hypoxia causes sustained pulmonary vasoconstriction (HPV) that may contributes to the elevated PVR in patients with pulmonary hypertension associated with hypoxia and lung diseases and in residents living in high altitude areas. Little is known about the molecular and cellular mechanisms, which underlie hypoxic pulmonary vasoconstriction and the development and progression of pulmonary hypertension.Methods and ResultsTo determine the functional relevance of hypoxia and hypoxia-inducible factors (HIFs) in the development of acute HPV, we compared high K+-induced increase in pulmonary arterial pressure (PAP) and acute alveolar hypoxia-mediated increase in PAP in isolated perfused and ventilated lungs between wild type (WT) and HIF1α or HIF2α conditional knockout (KO) mice. Conditional and inducible deletion of HIF1α or HIF2α in endothelial cells (HIF1αEC−/−, or HIF2αEC−/−), but not smooth muscle cells, dramatically protected mice from hypoxia-induced pulmonary hypertension. We analyzed the hypoxia-induced response in isolated lungs from WT and KO mice. Ventilation of lungs from mice with 1% O2 provoked a vasoconstrictor response and reached to the plateau within 4 min in both WT, HIF1αEC−/−, and HIF2αEC−/− mice. Normoxic vascular ton were not affected by deletion of HIF1α or HIF2α and there is no difference of vasoconstriction induced by high K+ between WT and KO mice.ConclusionOur study has demonstrated that deletion of HIF1α or HIF2α in endothelial cells dramatically attenuate chronic hypoxia-induced pulmonary hypertension, but negligibly affect the acute hypoxia-induced pulmonary vasoconstriction. These results implicated that targets of endothelial HIFs signaling pathway may lead to novel therapeutic targets for chronic hypoxia-induced pulmonary hypertension but endothelial HIFs signaling are not involved in acute hypoxic pulmonary vasoconstriction.

scholarly journals HIF and pulmonary vascular responses to hypoxia

2014 ◽  
Vol 116 (7) ◽  
pp. 867-874 ◽  
Author(s):  
Larissa A. Shimoda ◽  
Steven S. Laurie
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Human Subjects ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxia Inducible Factors ◽  
Pulmonary Vascular Remodeling ◽  
Vascular Responses ◽  
Pulmonary Vasoconstriction ◽  
Oxygen Sensitive

In the lung, acute reductions in oxygen lead to hypoxic pulmonary vasoconstriction, whereas prolonged exposures to hypoxia result in sustained vasoconstriction, pulmonary vascular remodeling, and the development of pulmonary hypertension. Data from both human subjects and animal models implicate a role for hypoxia-inducible factors (HIFs), oxygen-sensitive transcription factors, in pulmonary vascular responses to both acute and chronic hypoxia. In this review, we discuss work from our laboratory and others supporting a role for HIF in modulating hypoxic pulmonary vasoconstriction and mediating hypoxia-induced pulmonary hypertension, identify some of the downstream targets of HIF, and assess the potential to pharmacologically target the HIF system.

Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

1996 ◽  
Vol 8 (3) ◽  
pp. 431 ◽  
Author(s):  
V DeMarco ◽  
JW Skimming ◽  
TM Ellis ◽  
S Cassin
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Circulation ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Minimum Concentration ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Inhaled No

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

Alterations in a redox oxygen sensing mechanism in chronic hypoxia

2001 ◽  
Vol 90 (6) ◽  
pp. 2249-2256 ◽  
Author(s):  
H. L. Reeve ◽  
E. Michelakis ◽  
D. P. Nelson ◽  
E. K. Weir ◽  
S. L. Archer
Keyword(s):  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Oxygen Species ◽  
Redox Sensor ◽  
Pulmonary Vasoconstriction ◽  
Activated Oxygen ◽  
Channel Expression ◽  
Pulmonary Arterial ◽  
Pulmonary Artery Smooth Muscle

The mechanism of acute hypoxic pulmonary vasoconstriction (HPV) may involve the inhibition of several voltage-gated K+channels in pulmonary artery smooth muscle cells. Changes in Po 2 can either be sensed directly by the channel(s) or be transmitted to the channel via a redox-based effector mechanism. In control lungs, hypoxia and rotenone acutely decrease production of activated oxygen species, inhibit K+channels, and cause constriction. Two-day and 3-wk chronic hypoxia (CH) resulted in a decrease in basal activated oxygen species levels, an increase in reduced glutathione, and loss of HPV and rotenone-induced constriction. In contrast, 4-aminopyridine- and KCl-mediated constrictions were preserved. After 3-wk CH, pulmonary arterial smooth muscle cell membrane potential was depolarized, K+ channel density was reduced, and acute hypoxic inhibition of whole cell K+ current was lost. In addition, Kv1.5 and Kv2.1 channel protein was decreased. These data suggest that chronic reduction of the cytosol occurs before changes in K+ channel expression. HPV may be attenuated in CH because of an impaired redox sensor.

Garlic prevents hypoxic pulmonary hypertension in rats

1998 ◽  
Vol 275 (2) ◽  
pp. L283-L287 ◽  
Author(s):  
Michael B. Fallon ◽  
Gary A. Abrams ◽  
Tarek T. Abdel-Razek ◽  
Jun Dai ◽  
Shi-Juan Chen ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Altitude ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Control Group ◽  
Nitric Oxide Synthase Inhibitor ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial ◽  
Synthase Inhibitor

Hypoxic pulmonary vasoconstriction underlies the development of high-altitude pulmonary edema. Anecdotal observations suggest a beneficial effect of garlic in preventing high-altitude symptoms. To determine whether garlic influences pulmonary vasoconstriction, we assessed the effect of garlic on pulmonary pressures in rats subjected to alveolar hypoxia and on vasoconstriction in isolated pulmonary arterial rings. Garlic gavage (100 mg/kg body wt) for 5 days resulted in complete inhibition of acute hypoxic pulmonary vasoconstriction compared with the control group. No difference in mean arterial pressure or heart rate response to hypoxia was seen between the groups. Garlic solution resulted in a significant dose-dependent vasorelaxation in both endothelium-intact and mechanically endothelium-disrupted pulmonary arterial rings. The administration of N G-nitro-l-arginine methyl ester (a nitric oxide synthase inhibitor) inhibited the vasodilatory effect of garlic by 80%. These studies document that garlic blocks hypoxic pulmonary hypertension in vivo and demonstrate a combination of endothelium-dependent and -independent mechanisms for the effect in pulmonary arterial rings.

Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase

2004 ◽  
Vol 287 (4) ◽  
pp. L656-L664 ◽  
Author(s):  
Karen A. Fagan ◽  
Masahiko Oka ◽  
Natalie R. Bauer ◽  
Sarah A. Gebb ◽  
D. Dunbar Ivy ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Rho Kinase ◽  
Hypoxic Pulmonary Hypertension ◽  
Pulmonary Vasoconstriction

RhoA GTPase mediates a variety of cellular responses, including activation of the contractile apparatus, growth, and gene expression. Acute hypoxia activates RhoA and, in turn, its downstream effector, Rho-kinase, and previous studies in rats have suggested a role for Rho/Rho-kinase signaling in both acute and chronically hypoxic pulmonary vasoconstriction. We therefore hypothesized that activation of Rho/Rho-kinase in the pulmonary circulation of mice contributes to acute hypoxic pulmonary vasoconstriction and chronic hypoxia-induced pulmonary hypertension and vascular remodeling. In isolated, salt solution-perfused mouse lungs, acute administration of the Rho-kinase inhibitor Y-27632 (1 × 10−5 M) attenuated hypoxic vasoconstriction as well as that due to angiotensin II and KCl. Chronic treatment with Y-27632 (30 mg·kg−1·day−1) via subcutaneous osmotic pump decreased right ventricular systolic pressure, right ventricular hypertrophy, and neomuscularization of the distal pulmonary vasculature in mice exposed to hypobaric hypoxia for 14 days. Analysis of a small number of proximal pulmonary arteries suggested that Y-27632 treatment reduced the level of phospho-CPI-17, a Rho-kinase target, in hypoxic lungs. We also found that endothelial nitric oxide synthase protein in hypoxic lungs was augmented by Y-27632, suggesting that enhanced nitric oxide production might have played a role in the Y-27632-induced attenuation of chronically hypoxic pulmonary hypertension. In conclusion, Rho/Rho-kinase activation is important in the effects of both acute and chronic hypoxia on the pulmonary circulation of mice, possibly by contributing to both vasoconstriction and vascular remodeling.

Role of leukotriene C4 in pulmonary hypertension: platelet-activating factor vs. hypoxia

1990 ◽  
Vol 68 (4) ◽  
pp. 1628-1633 ◽  
Author(s):  
D. Davidson ◽  
M. Singh ◽  
G. F. Wallace
Keyword(s):  
Pulmonary Hypertension ◽  
Arterial Pressure ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Platelet Activating Factor ◽  
Lung Parenchyma ◽  
Base Line ◽  
Leukotriene C4 ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

The aim of this study was to determine whether leukotriene C4 (LTC4) is a mediator of hypoxic pulmonary vasoconstriction. We hypothesized that similar increases in LTC4, detected in the lung parenchyma and pulmonary vascular compartment during cyclooxygenase blockade with indomethacin (INDO), would be observed during an equal increase in pulmonary arterial pressure caused by acute alveolar hypoxia (HYP, 100% N2) or platelet-activating factor (PAF, 10 micrograms into the pulmonary artery). Rat lungs were perfused at constant flow in vitro with an albumin-Krebs-Henseleit solution. Mean pulmonary arterial pressure (n = 6 per group) increased from a base line of 10.9 +/- 1.2 to 15.8 +/- 2.1 (HYP + INDO) and 15.5 +/- 1.9 (SE) Torr (PAF + INDO). LTC4 levels increased only in response to PAF + INDO; perfusate levels increased from 0.4 +/- 0.07 to 5.3 +/- 1.1 ng/40 ml, and lung parenchymal levels increased from 1.9 +/- 0.07 to 22.8 +/- 5.3 ng/lung. Diethylcarbamazine (lipoxygenase inhibitor) reduced PAF-induced lung parenchymal levels of LTC4 by 68% and pulmonary hypertension by 63%. We conclude that 1) LTC4 is not a mediator of hypoxic pulmonary vasoconstriction and 2) intravascular PAF is a potent stimulus for LTC4 production in the lung parenchyma.

scholarly journals Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2

2013 ◽  
Vol 305 (2) ◽  
pp. L154-L164 ◽  
Author(s):  
Jun Wan ◽  
Aya Yamamura ◽  
Adriana M. Zimnicka ◽  
Guillaume Voiriot ◽  
Kimberly A. Smith ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Chronic Hypoxia ◽  
Isometric Force ◽  
Force Measurements ◽  
Pulmonary Vasoconstriction ◽  
High K ◽  
Voltage Dependent ◽  
Important Pathway ◽  
Pulmonary Artery Smooth Muscle

Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca2+ influx through voltage-dependent Ca2+ channels (VDCC) is an important pathway for the regulation of [Ca2+]cyt. The potential role for L- and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K+- and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K+- and U-46619-induced Ca2+ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K+- and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltage-dependent L-type α1C-subunit (Cav1.2) and T-type α1H-subunit (Cav3.2) upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2.

Hypoxic Pulmonary Vasoconstriction and Chronic Lung Disease

2013 ◽  
Vol 12 (3) ◽  
pp. 135-144 ◽  
Author(s):  
Erik R. Swenson
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Disease ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
World Health ◽  
Disease States ◽  
Pulmonary Vasoconstriction ◽  
Local Ventilation ◽  
Pulmonary Vascular Endothelium ◽  
Health And Disease ◽  
Health Organization

Hypoxic vasoconstriction in the lung is a unique and fundamental characteristic of the pulmonary circulation. It functions in health and disease states to better preserve ventilation-perfusion matching by diverting blood flow to better ventilated regions when local ventilation is compromised. As more areas of lung become hypoxic either with high altitude or global lung disease, then hypoxic pulmonary vasoconstriction (HPV) becomes less effective in ventilation-perfusion matching and can lead to pulmonary hypertension. HPV is intrinsic to the vascular smooth muscle and its mechanisms remain poorly understood. In addition, the pulmonary vascular endothelium, red cells, lung innervation, and numerous circulating vasoactive agents also affect the strength of HPV. This review will discuss the pathophysiology of HPV and address its role in pulmonary hypertension associated with World Health Organization Group 3 diseases. When sustained beyond many hours, HPV may initiate pulmonary vascular remodeling and lead to more fixed and less oxygen-responsive pulmonary hypertension if the hypoxic stimulus is maintained.

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

2005 ◽  
Vol 289 (1) ◽  
pp. L5-L13 ◽  
Author(s):  
Letitia Weigand ◽  
Joshua Foxson ◽  
Jian Wang ◽  
Larissa A. Shimoda ◽  
J. T. Sylvester
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Arteries ◽  
Cation Channels ◽  
Pulmonary Vasoconstriction ◽  
Nonselective Cation Channels ◽  
Pressor Responses ◽  
Intracellular Ca ◽  
Pulmonary Arterial

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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