Chronic hypoxia-induced pulmonary hypertension in rat: the best animal model for studying pulmonary vasoconstriction and vascular medial hypertrophy

2010 ◽  
Vol 7 (3-4) ◽  
pp. 83-88 ◽  
Author(s):  
Lan Zhao
Keyword(s):  
Animal Model ◽  
Pulmonary Hypertension ◽  
Chronic Hypoxia ◽  
Pulmonary Vasoconstriction ◽  
Medial Hypertrophy

Sustained membrane depolarization and pulmonary artery smooth muscle cell proliferation

2000 ◽  
Vol 279 (5) ◽  
pp. C1540-C1549 ◽  
Author(s):  
Oleksandr Platoshyn ◽  
Vera A. Golovina ◽  
Colleen L. Bailey ◽  
Alisa Limsuwan ◽  
Stefanie Krick ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Cell Growth ◽  
Pulmonary Artery ◽  
Critical Role ◽  
Membrane Depolarization ◽  
Kv Channels ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Artery Smooth Muscle ◽  
Medial Hypertrophy

Pulmonary vasoconstriction and vascular medial hypertrophy greatly contribute to the elevated pulmonary vascular resistance in patients with pulmonary hypertension. A rise in cytosolic free Ca2+ ([Ca2+]cyt) in pulmonary artery smooth muscle cells (PASMC) triggers vasoconstriction and stimulates cell growth. Membrane potential ( E m) regulates [Ca2+]cyt by governing Ca2+influx through voltage-dependent Ca2+ channels. Thus intracellular Ca2+ may serve as a shared signal transduction element that leads to pulmonary vasoconstriction and vascular remodeling. In PASMC, activity of voltage-gated K+(Kv) channels regulates resting E m. In this study, we investigated whether changes of Kv currents [ I K(V)], E m, and [Ca2+]cyt affect cell growth by comparing these parameters in proliferating and growth-arrested PASMC. Serum deprivation induced growth arrest of PASMC, whereas chelation of extracellular Ca2+ abolished PASMC growth. Resting [Ca2+]cyt was significantly higher, and resting E m was more depolarized, in proliferating PASMC than in growth-arrested cells. Consistently, whole cell I K(V) was significantly attenuated in PASMC during proliferation. Furthermore, E mdepolarization significantly increased resting [Ca2+]cyt and augmented agonist-mediated rises in [Ca2+]cyt in the absence of extracellular Ca2+. These results demonstrate that reduced I K(V), depolarized E m, and elevated [Ca2+]cyt may play a critical role in stimulating PASMC proliferation. Pulmonary vascular medial hypertrophy in patients with pulmonary hypertension may be partly caused by a membrane depolarization-mediated increase in [Ca2+]cyt in PASMC.

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.

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.

Hypoxic pulmonary vasoconstriction: role of ion channels

2005 ◽  
Vol 98 (1) ◽  
pp. 415-420 ◽  
Author(s):  
Joseph R. H. Mauban ◽  
Carmelle V. Remillard ◽  
Jason X.-J. Yuan
Keyword(s):  
Ion Channels ◽  
Structural Changes ◽  
Chronic Hypoxia ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Acute Hypoxia ◽  
Pulmonary Vasculature ◽  
Cellular Mechanisms ◽  
Pulmonary Vasoconstriction ◽  
Intracellular Ca ◽  
Medial Hypertrophy

Acute hypoxia induces pulmonary vasoconstriction and chronic hypoxia causes structural changes of the pulmonary vasculature including arterial medial hypertrophy. Electro- and pharmacomechanical mechanisms are involved in regulating pulmonary vasomotor tone, whereas intracellular Ca2+ serves as an important signal in regulating contraction and proliferation of pulmonary artery smooth muscle cells. Herein, we provide a basic overview of the cellular mechanisms involved in the development of hypoxic pulmonary vasoconstriction. Our discussion focuses on the roles of ion channels permeable to K+ and Ca2+, membrane potential, and cytoplasmic Ca2+ in the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary 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.

Comparative physiology of hypoxic pulmonary hypertension: historical clues from brisket disease

2005 ◽  
Vol 98 (3) ◽  
pp. 1092-1100 ◽  
Author(s):  
Jann Rhodes
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Chronic Hypoxia ◽  
Splice Variants ◽  
Pulmonary Arteries ◽  
High Mountain ◽  
Hypoxic Pulmonary Hypertension ◽  
And Gender ◽  
Medial Hypertrophy

Some of the most valuable contributions to science have come about serendipitously, and, in 1913, when George Glover and Issac Newsom were commissioned by Colorado cattle ranchers to study high mountain disease, there was no way to anticipate the tremendous impact they would have on the study of high-altitude cardiopulmonary physiology. It was through the study of this agricultural malady that the correlation between chronic hypoxia, pulmonary hypertension, medial hypertrophy of the small pulmonary arteries, and right ventricular (RV) hypertrophy was recognized. The amount of vascular smooth muscle comprising the medial layer of pulmonary arteries varies significantly across species and can be used to predict the magnitude of pulmonary hypertension and RV hypertrophy elicited in response to chronic hypoxia. Within species, age and gender both significantly influence the severity of chronic hypoxic pulmonary hypertension and RV hypertrophy. However, despite all that we now know about hypoxic pulmonary hypertension, the specific mechanism(s) that differentiate the hypo- from the hyperresponder have yet to be elucidated. Adventitial fibroblast differentiation, circulating vascular progenitor cells, the presence or absence of specific vascular smooth muscle phenotypes, the upregulation or downregulation of vasoactive mediators, splice variants of oxygen-sensitive transcription factors, upregulation of growth factors, Ca2+ sensitization, and/or the Rho/Rho-kinases signaling cascade could all potentially play a role in determining the extent of the vascular response to hypoxia within a species. Understanding the mechanisms that determine why some people, as well as some animals, exhibit a marked susceptibility to hypoxia is an important endeavor with far-reaching implications.

Chronic hypoxia decreases KV channel expression and function in pulmonary artery myocytes

2001 ◽  
Vol 280 (4) ◽  
pp. L801-L812 ◽  
Author(s):  
Oleksandr Platoshyn ◽  
Ying Yu ◽  
Vera A. Golovina ◽  
Sharon S. McDaniel ◽  
Stefanie Krick ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Mrna Expression ◽  
Chronic Hypoxia ◽  
Critical Role ◽  
Α Subunit ◽  
Kv Channel ◽  
Pulmonary Vasoconstriction ◽  
Channel Expression ◽  
Medial Hypertrophy ◽  
And Function

Activity of voltage-gated K+ (KV) channels regulates membrane potential ( E m) and cytosolic free Ca2+concentration ([Ca2+]cyt). A rise in [Ca2+]cyt in pulmonary artery (PA) smooth muscle cells (SMCs) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. Chronic hypoxia (Po 2 30–35 mmHg for 60–72 h) decreased mRNA expression of KV channel α-subunits (Kv1.1, Kv1.5, Kv2.1, Kv4.3, and Kv9.3) in PASMCs but not in mesenteric artery (MA) SMCs. Consistently, chronic hypoxia attenuated protein expression of Kv1.1, Kv1.5, and Kv2.1; reduced KV current [ I K(V)]; caused E mdepolarization; and increased [Ca2+]cyt in PASMCs but negligibly affected KV channel expression, increased I K(V), and induced hyperpolarization in MASMCs. These results demonstrate that chronic hypoxia selectively downregulates KV channel expression, reduces I K(V), and induces E mdepolarization in PASMCs. The subsequent rise in [Ca2+]cyt plays a critical role in the development of pulmonary vasoconstriction and medial hypertrophy. The divergent effects of hypoxia on KV channel α-subunit mRNA expression in PASMCs and MASMCs may result from different mechanisms involved in the regulation of KV channel gene expression.

scholarly journals Cytochrome P450 Epoxygenase-Dependent Activation of TRPV4 Channel Participates in Enhanced Serotonin-Induced Pulmonary Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yang Xia ◽  
Lexin Xia ◽  
Zhou Jin ◽  
Rui Jin ◽  
Omkar Paudel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cytochrome P450 ◽  
Transient Receptor Potential ◽  
Chronic Hypoxia ◽  
Pulmonary Arteries ◽  
Specific Inhibitor ◽  
Receptor Potential ◽  
Inhibitory Effect ◽  
Transient Receptor Potential Vanilloid ◽  
Pulmonary Vasoconstriction

Transient receptor potential vanilloid 4 (TRPV4) is a multi-functional non-selective channel expressed in pulmonary vasculatures. TRPV4 contributes to serotonin- (5-HT-) induced pulmonary vasoconstriction and is responsible in part for the enhanced 5-HT response in pulmonary arteries (PAs) of chronic hypoxia mice. Epoxyeicosatrienoic acid (EET) is an endogenous agonist of TRPV4 and is known to regulate vasoreactivity. The levels of EETs, the expression of cytochrome P450 (CYP) epoxygenase for EET production, and epoxide hydrolase for EET degradation are altered by chronic hypoxia. Here, we examined the role of EET-dependent TRPV4 activation in the 5-HT-mediated PA contraction. In PAs of normoxic mice, inhibition of TRPV4 with a specific inhibitor HC-067047 caused a decrease in the sensitivity of 5-HT-induced PA contraction without affecting the maximal contractile response. Application of the cytochrome P450 epoxygenase inhibitor MS-PPOH had no effect on the vasoreactivity to 5-HT. In contrast, inhibition of CYP epoxygenase or TRPV4 both attenuated the 5-HT-elicited maximal contraction to a comparable level in PAs of chronic hypoxic mice. Moreover, the inhibitory effect of MS-PPOH on the 5-HT-induced contraction was obliterated in PAs of chronic hypoxic trpv4-/- mice. These results suggest that TRPV4 contributes to the enhanced 5-HT-induced vasoconstriction in chronic hypoxic PAs, in part via the CYP-EET-TRPV4 pathway. Our results further support the notion that manipulation of TRPV4 function may offer a novel therapeutic strategy for the treatment of hypoxia-related pulmonary hypertension.

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.

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