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.

Abstract 2616: Role of the Soluble Epoxide Hydrolase in Hypoxic Pulmonary Vasoconstriction and Pulmonary Vascular Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Benjamin Keserü ◽  
Beate Fisslthaler ◽  
Ingrid Fleming
Keyword(s):  
Vascular Remodeling ◽  
Epoxide Hydrolase ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Soluble Epoxide Hydrolase ◽  
Pulmonary Vasculature ◽  
Resistance Arteries ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Vasoconstriction

The soluble epoxide hydrolase (sEH), which is expressed in pulmonary artery smooth muscle cells, metabolizes cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) to their less active diols. Preliminary findings indicate a role of the sEH on hypoxic pulmonary vasoconstriction (HPV) and a vasoconstrictor role of EETs in the pulmonary vasculature. Here we assessed the influence of hypoxia on the expression of the sEH, acute HPV and pulmonary vascular remodeling. In lungs from wild-type mice (WT), exposure to hypoxia (FiO 2 = 0.1) for 21 days decreased the expression of the sEH by 70% (RT-PCR), and increased the number of partially and fully muscularised resistance arteries (by 3-fold). In isolated lungs, pre-exposure to chronic hypoxia significantly increased baseline perfusion pressures (1.3-fold) and potentiated the acute HPV (1.5-fold). While an sEH inhibitor (1-adamantyl-3-cyclohexylurea; ACU) potentiated acute HPV in lungs from mice maintained in normoxic conditions, it had no effect on HPV in lungs from mice exposed to hypoxia. The EET antagonist, 14,15-EEZE, abolished the sEH inhibitor-dependent increase in acute HPV in normoxic lungs. Under normoxic conditions the muscularization of small pulmonary arteries was greater in lungs from sEH −/− mice than in lungs from WT mice and chronic hypoxia further increased the number of fully and partially muscularized arteries in these animals. sEH −/− mice also displayed an enhanced acute HPV (1.5-fold), compared to that observed in WT mice and chronic exposure to hypoxia did not further potentiate acute HPV. Taken together, these data indicate that the sEH is involved in hypoxia-induced pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction.

PAF antagonists inhibit pulmonary vascular remodeling induced by hypobaric hypoxia in rats

1992 ◽  
Vol 73 (3) ◽  
pp. 1084-1092 ◽  
Author(s):  
S. Ono ◽  
J. Y. Westcott ◽  
N. F. Voelkel
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Paf Antagonists ◽  
Isolated Lungs

Chronic hypoxia causes pulmonary hypertension and pulmonary vascular remodeling in rats. Because platelet-activating factor (PAF) levels increase in lung lavage fluid and in plasma from chronically hypoxic rats, we examined the effect of two specific, structurally unrelated PAF antagonists, WEB 2170 and BN 50739, on hypoxia-induced pulmonary vascular remodeling. Treatment with either agent reduced hypoxia-induced pulmonary hypertension and right ventricular hypertrophy at 3 wk of hypoxic exposure (simulated altitude 5,100 m) but did not affect cobalt (CoCl2)-induced pulmonary hypertension. The PAF antagonists had no effect on the hematocrit of normoxic or chronically hypoxic rats or CoCl2-treated rats. Hypoxia-induced pulmonary hypertension was associated with an increase in the vessel wall thickness of the muscular arteries and reduction in the number of peripheral arterioles. In WEB 2170-treated rats, these changes were significantly less severe than those observed in untreated chronically hypoxic rats. PAF receptor blockade had no acute hemodynamic effects; i.e., it did not affect pulmonary arterial pressure or cardiac output nor did it affect the magnitude of acute hypoxic pulmonary vasoconstriction in awake normoxic or chronically hypoxic rats. Isolated lungs from chronically hypoxic rats showed a pressor response to the chemotactic tripeptide N-formyl-Met-Leu-Phe (fMLP) and an increase in the number of leukocytes lavaged from the pulmonary circulation. In vivo treatment with WEB 2170 significantly reduced the fMLP-induced pressor response compared with that observed in isolated lungs from untreated chronically hypoxic rats. These results suggest that PAF contributes to the development of chronic pulmonary hypertension induced by chronic hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats

2003 ◽  
Vol 285 (1) ◽  
pp. L199-L208 ◽  
Author(s):  
Jan Herget ◽  
Jana Novotná ◽  
Jana Bíbová ◽  
Viera Povýšilová ◽  
Marie Vaňková ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Chronic Hypoxia ◽  
Causative Factor ◽  
Systemic Arterial Pressure ◽  
Collagenolytic Activity ◽  
Pulmonary Vascular Remodeling ◽  
Arterial Blood ◽  
Fraction Of Inspired Oxygen ◽  
Lung Vessels

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 ± 3 mmHg in hypoxic controls, 24 ± 1 mmHg in Batimastat-treated hypoxic rats, and 16 ± 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

Divergent contractile and structural responses of the murine PKC-ε null pulmonary circulation to chronic hypoxia

2005 ◽  
Vol 289 (6) ◽  
pp. L1083-L1093 ◽  
Author(s):  
C. M. Littler ◽  
C. A. Wehling ◽  
M. J. Wick ◽  
K. A. Fagan ◽  
C. D. Cool ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Circulation ◽  
Vascular Remodeling ◽  
Vascular Tone ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Structural Response ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Remodeling

Loss of PKC-ε limits the magnitude of acute hypoxic pulmonary vasoconstriction (HPV) in the mouse. Therefore, we hypothesized that loss of PKC-ε would decrease the contractile and/or structural response of the murine pulmonary circulation to chronic hypoxia (Hx). However, the pattern of lung vascular responses to chronic Hx may or may not be predicted by the acute HPV response. Adult PKC-ε wild-type (PKC-ε+/+), heterozygous null, and homozygous null (PKC-ε−/−) mice were exposed to normoxia or Hx for 5 wk. PKC-ε−/− mice actually had a greater increase in right ventricular (RV) systolic pressure, RV mass, and hematocrit in response to chronic Hx than PKC-ε+/+ mice. In contrast to the augmented PA pressure and RV hypertrophy, pulmonary vascular remodeling was increased less than expected (i.e., equal to PKC-ε+/+ mice) in both the proximal and distal PKC-ε−/− pulmonary vasculature. The contribution of increased vascular tone to this pulmonary hypertension (PHTN) was assessed by measuring the acute vasodilator response to nitric oxide (NO). Acute inhalation of NO reversed the increased PA pressure in hypoxic PKC-ε−/− mice, implying that the exaggerated PHTN may be due to a relative deficiency in nitric oxide synthase (NOS). Despite the higher PA pressure, chronic Hx stimulated less of an increase in lung endothelial (e) and inducible (i) NOS expression in PKC-ε−/− than PKC-ε+/+ mice. In contrast, expression of nNOS in PKC-ε+/+ mice decreased in response to chronic Hx, while lung levels in PKC-ε−/− mice remained unchanged. In summary, loss of PKC-ε results in increased vascular tone, but not pulmonary vascular remodeling in response to chronic Hx. Blunting of Hx-induced eNOS and iNOS expression may contribute to the increased vascular tone. PKC-ε appears to be an important signaling intermediate in the hypoxic regulation of each NOS isoform.

scholarly journals HIF2α–arginase axis is essential for the development of pulmonary hypertension

2016 ◽  
Vol 113 (31) ◽  
pp. 8801-8806 ◽  
Author(s):  
Andrew S. Cowburn ◽  
Alexi Crosby ◽  
David Macias ◽  
Cristina Branco ◽  
Renato D. D. R. Colaço ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Remodeling ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Systolic Pressure ◽  
Hypoxic Exposure ◽  
Pulmonary Vascular Remodeling ◽  
Ventricular Systolic Pressure ◽  
Pulmonary Endothelium ◽  
Arginase 1

Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.

Chronic hypercapnia inhibits hypoxic pulmonary vascular remodeling

2000 ◽  
Vol 278 (2) ◽  
pp. H331-H338 ◽  
Author(s):  
Henry Ooi ◽  
Elaine Cadogan ◽  
Michèle Sweeney ◽  
Katherine Howell ◽  
R. G. O'Regan ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Right Ventricular ◽  
Vascular Remodeling ◽  
Ventricular Hypertrophy ◽  
Chronic Hypoxia ◽  
Pulmonary Arterial Pressure ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Right Ventricular Hypertrophy ◽  
Pulmonary Vascular Remodeling ◽  
Pulmonary Arterial

Chronic hypercapnia is commonly found in patients with severe hypoxic lung disease and is associated with a greater elevation of pulmonary arterial pressure than that due to hypoxia alone. We hypothesized that hypercapnia worsens hypoxic pulmonary hypertension by augmenting pulmonary vascular remodeling and hypoxic pulmonary vasoconstriction (HPV). Rats were exposed to chronic hypoxia [inspiratory O2 fraction ([Formula: see text]) = 0.10], chronic hypercapnia (inspiratory CO2 fraction = 0.10), hypoxia-hypercapnia ([Formula: see text]= 0.10, inspiratory CO2 fraction = 0.10), or room air. After 1 and 3 wk of exposure, muscularization of resistance blood vessels and hypoxia-induced hematocrit elevation were significantly inhibited in hypoxia-hypercapnia compared with hypoxia alone ( P < 0.001, ANOVA). Right ventricular hypertrophy was reduced in hypoxia-hypercapnia compared with hypoxia at 3 wk ( P < 0.001, ANOVA). In isolated, ventilated, blood-perfused lungs, basal pulmonary arterial pressure after 1 wk of exposure to hypoxia (20.1 ± 1.8 mmHg) was significantly ( P < 0.01, ANOVA) elevated compared with control conditions (12.1 ± 0.1 mmHg) but was not altered in hypoxia-hypercapnia (13.5 ± 0.9 mmHg) or hypercapnia (11.8 ± 1.3 mmHg). HPV ([Formula: see text] = 0.03) was attenuated in hypoxia, hypoxia-hypercapnia, and hypercapnia compared with control ( P < 0.05, ANOVA). Addition of N ω-nitro-l-arginine methyl ester (10−4 M), which augmented HPV in control, hypoxia, and hypercapnia, significantly reduced HPV in hypoxia-hypercapnia. Chronic hypoxia caused impaired endothelium-dependent relaxation in isolated pulmonary arteries, but coexistent hypercapnia partially protected against this effect. These findings suggest that coexistent hypercapnia inhibits hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy, reduces HPV, and protects against hypoxia-induced impairment of endothelial function.

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