Development Of Hypoxic Pulmonary Vasoconstriction Research Articles

Inflammation in Pulmonary Hypertension and Edema Induced by Hypobaric Hypoxia Exposure.

Exposure to high altitudes generates a decrease in the partial pressure of oxygen, triggering a hypobaric hypoxic condition. This condition produces pathophysiologic alterations in an organism. In the lung, one of the principal responses to hypoxia is the development of hypoxic pulmonary vasoconstriction (HPV), which improves gas exchange. However, when HPV is exacerbated, it induces high-altitude pulmonary hypertension (HAPH). Another important illness in hypobaric hypoxia is high-altitude pulmonary edema (HAPE), which occurs under acute exposure. Several studies have shown that inflammatory processes are activated in high-altitude illnesses, highlighting the importance of the crosstalk between hypoxia and inflammation. The aim of this review is to determine the inflammatory pathways involved in hypobaric hypoxia, to investigate the key role of inflammation in lung pathologies, such as HAPH and HAPE, and to summarize different anti-inflammatory treatment approaches for these high-altitude illnesses. In conclusion, both HAPE and HAPH show an increase in inflammatory cell infiltration (macrophages and neutrophils), cytokine levels (IL-6, TNF-α and IL-1β), chemokine levels (MCP-1), and cell adhesion molecule levels (ICAM-1 and VCAM-1), and anti-inflammatory treatments (decreasing all inflammatory components mentioned above) seem to be promising mitigation strategies for treating lung pathologies associated with high-altitude exposure.

Impact of Zinc on Oxidative Signaling Pathways in the Development of Pulmonary Vasoconstriction Induced by Hypobaric Hypoxia.

Hypobaric hypoxia is a condition that occurs at high altitudes (>2500 m) where the partial pressure of gases, particularly oxygen (PO2), decreases. This condition triggers several physiological and molecular responses. One of the principal responses is pulmonary vascular contraction, which seeks to optimize gas exchange under this condition, known as hypoxic pulmonary vasoconstriction (HPV); however, when this physiological response is exacerbated, it contributes to the development of high-altitude pulmonary hypertension (HAPH). Increased levels of zinc (Zn2+) and oxidative stress (known as the “ROS hypothesis”) have been demonstrated in the vasoconstriction process. Therefore, the aim of this review is to determine the relationship between molecular pathways associated with altered Zn2+ levels and oxidative stress in HPV in hypobaric hypoxic conditions. The results indicate an increased level of Zn2+, which is related to increasing mitochondrial ROS (mtROS), alterations in nitric oxide (NO), metallothionein (MT), zinc-regulated, iron-regulated transporter-like protein (ZIP), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-induced protein kinase C epsilon (PKCε) activation in the development of HPV. In conclusion, there is an association between elevated Zn2+ levels and oxidative stress in HPV under different models of hypoxia, which contribute to understanding the molecular mechanism involved in HPV to prevent the development of HAPH.

Influence of type 2 diabetes mellitus on the development of hypoxic pulmonary vasoconstriction

Hypoxia is currently considered to be an universal factor involved in the development of complications in many diseases including diabetes mellitus (DM). Acute hypoxia causes a systemic reaction with the large circulatory system developing vasodilation and the lesser circulatory system arteries developinghypoxic pulmonary vasoconstriction (HPV), which demonstrates the arteries' ability to regulate pulmonary circulation and maintain normal ventilation-perfusion ratio. Lack of the adequate response to hypoxic effects may be an additional mechanism for the diabetic complications in the cardiovascular system. Despite years of study, the mechanisms of HPV remain largely unclear, as does the effect of diabetes on pulmonary artery reactivity.The aim of the study was to evaluate the effect of high-fat diet and diabetes on the development of the HPV reaction in vivo and in vitro.Studies in rats divided into three groups (control group, a group of rats on a high-fat diet (HFD), and a group of animals with experimental type 2 diabetes mellitus (T2DM)) showed that in rats kept on the high-fat diet, an injection of streptozotocin leads to significant increase in blood glucose levels. In rats kept on the high-fat diet only, this parameter did not differ from the levels in the control animals. In rats kept on HFD and in rats with T2DM model, the right ventricular pressure was significantly higher compared to the control rats.The lung ventilation with a hypoxic gas mixture led to decrease in blood pressure in the systemic circulation in animals of all groups. In the control rats, the pressure in the right ventricular cavity of the heart increased indicating the development of hypoxic pulmonary vasoconstriction. In HFD rats, hypoxic hypoxiahad virtually no effect on the right ventricular pressure. In T2DM rats, an inversion of the hypoxic pulmonary vasoconstriction reaction with decrease in the right ventricular pressure was observed.These results have been confirmed in the in vitro experiments. In lung sections, the responses of the intrapulmonary arteries to hypoxic effects were multi-directional: the pulmonary artery luminal area decreased in the control animals, almost did not change in HFD animals, and increased in T2DM animals.In the rats with experimental diabetes mellitus, the contractile responses of the pulmonary artery ring segments to hypoxia were significantly suppressed compared to the vessels from the control animals.Finding out the exact mechanisms involved in the inversion of the pulmonary vasoconstriction response in diabetes will contribute to a better understanding of the fundamental pathophysiological processes that will promote development of pathogenetically justified approaches to the treatment of this disease and its complications.

Hypoxic Pulmonary Vasoconstriction in Isolated Mouse Lungs

BackgroundHypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism of lung to ensure maximal gas exchange and blood oxygenation. Persistent and global alveolar hypoxia leads to sustained vasoconstriction and vascular remodeling causing pulmonary hypertension. It has been demonstrated that acute HPV is initiated by an increase in cytosolic [Ca2+] ([Ca2+]cyt) in pulmonary arterial smooth muscle cells (PASMC) and modulated by factors released from endothelium. Acute HPV is well reserved in isolated perfused/ventilated lungs, whereas HPV in isolated pulmonary arterial rings shows different pattern in comparison to HPV in intact animals and humans. In this study, we aimed to use isolated perfused/ventilated mouse lungs to further study potential mechanisms involved in development of HPV.MethodsC57BL/6 mice (male, 8–10 weeks old) were anesthetized by pentobarbital sodium (120 mg/kg). After tracheostomy, isolated lungs were immediately ventilated with normoxic gas (21% O2/5% CO2) using a rodent ventilator (80 breaths/min with a tidal volume of 250 μl). The mice were then placed in an isolated lung system chamber with a heated water jacket at 37°C. After tracheal intubation, the chest was opened and a catheter was inserted into the main PA via the right ventricle to measure PAP. The lung vasculature was consistently superfused with physiological salt solution (PSS) via a pump while lung airway and alveoli were ventilated with normoxic or hypoxic gas. Before experimentation, the isolated lung was first superfused with the 40 mM K+‐containing PSS (40K) to stabilize the basal PAP. The lung was then repetitively challenged by ventilation of hypoxic gas (1% O2 in N2, for 4 min) to induce an increase in PAP (due to HPV). Pharmacological effects of various inhibitors on HPV were examined by superfusion of PSS containing the inhibitors while the lung was ventilated with hypoxic gas.ResultsOur results show that HPV was dependent on Ca2+ influx through a) nifedipine‐sensitive L‐type voltage‐dependent Ca2+ channels; b) SKF‐sensitive non‐selective cation channels; and c) TRP channels like TRPC6, TRPV1 and TRPP. HPV in isolated perfused lung was also significantly inhibited by blocking Ca2+‐sensing receptors (CaSR) and Notch receptors and by extracellular Mg2+ and Mn2+. Interestingly, blockade of Ca2+‐activated Cl− channels and inhibition of muscarinic receptors and endothelin receptors had little effect on HPV. Furthermore, inhibition of nitric oxide synthase (eNOS) potentiated HPV.ConclusionAn increase in [Ca2+]cyt due to Ca2+ influx through various Ca2+‐permeable cation channels in PASMC influx is required for the initiation of acute HPV. Both voltage‐gated Ca2+ channels (e.g., CaV1.2) and receptor‐operated Ca2+ channels (TRPC6/V1/P) are involved in mediating Ca2+ influx to induce HPV. G protein‐coupled receptor/CaSR‐mediated synthesis of intracellular signaling molecules (e.g., diacylglycerol and inositol 1, 4, 5‐trisphosphate) and Notch‐associated cell‐to‐cell interaction also play important roles in HPV. These data indicate that multiple mechanisms are involved in the initiation and regulation of HPV.Support or Funding InformationNIH NIHLBI HL135807

G Protein Coupled Receptor 75 and Its Role in Pulmonary Hypertension

Pulmonary Hypertension (PH) is a multifactorial disease with poor prognosis and inadequate treatment. Recent studies have shown that the orphan G Protein Coupled Receptor 75 (GPR75) is upregulated in the pulmonary vessels of PH patients, especially in females. Therefore, we hypothesized that GPR75 knock out (GPR75KO) mice will be protected from developing PH. We placed 3‐month‐old female GPR75KO (n=6) and control C57BL/C mice (n=10) in a hypoxic chamber with 10% Oxygen or at atmospheric oxygen for 5 weeks. At the end of 5 weeks, we performed echocardiograms and right heart catheterizations. GPR75KO mice were protected from developing PH (Right Ventricle Systolic Pressure (RVSP) of 26mmHg and Right Ventricle Diastolic Pressure (RVDP) of 2 mmHg), while C57BL/C mice developed PH under hypoxia (RSVP and RDVP of 56mmHg and 12mmHg, respectively). Wire myography was performed on isolated intra‐lobar pulmonary arteries from GPR75KO mice (n=3) and WT mice (n=31). Hypoxic pulmonary vasoconstriction (HPV) was abolished in GPR75KO as compared to WT. HPV response in WT was blocked (P<0.05) by antibody against RANTES (CCL5), a putative GPR75 ligand. These results suggest GPR75 plays a major role in the development of HPV and PH.Support or Funding InformationThis study was supported by NIH grant 1RO1HL139793 (MLS).

Hypoxic pulmonary vasoconstriction is lacking in rats with type 1 diabetes.

Hypoxic pulmonary vasoconstriction (HPV) is the most important feature of intact lung circulation that matches local blood perfusion to ventilation. The main goal of this work was to study the effects of diabetes on the development of HPV in rats. The experimental design comprised diabetes mellitus induction by streptozotocin, video-morphometric measurements of the lumen area of intrapulmonary arteries (iPAs) using perfused lung tissue slices and patch-clamp techniques. It was shown that iPA lumen size was significantly reduced under physical and chemical hypoxia (7-10mm Hg) in normal iPA, but, on the contrary, it clearly increased in diabetic lung slices. The amplitude of the outward K+ current in diabetic iPAs smooth muscle cells (SMCs) was two-fold greater than that seen in healthy cells. Chemical hypoxia led to significant decrease in the amplitude of the K+ outward current in healthy iPA SMCs while it was without effect in diabetic cells. The data obtained clearly indicate a significant dysregulation of vascular tone in pulmonary circulation under diabetes, ie diabetes damages the adaptive mechanism for regulating blood flow from poorly ventilated to better ventilated regions of the lung under hypoxia. This effect could be clinically important for patients with diabetes who have acute or chronic lung diseases associated with the lack of blood oxygenation.

Notch Activation of Ca(2+) Signaling in the Development of Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension.

Hypoxic pulmonary vasoconstriction (HPV) is an important physiological response that optimizes the ventilation/perfusion ratio. Chronic hypoxia causes vascular remodeling, which is central to the pathogenesis of hypoxia-induced pulmonary hypertension (HPH). We have previously shown that Notch3 is up-regulated in HPH and that activation of Notch signaling enhances store-operated Ca(2+) entry (SOCE), an important mechanism that contributes to pulmonary arterial smooth muscle cell (PASMC) proliferation and contraction. Here, we investigate the role of Notch signaling in HPV and hypoxia-induced enhancement of SOCE. We examined SOCE in human PASMCs exposed to hypoxia and pulmonary arterial pressure in mice using the isolated perfused/ventilated lung method. Wild-type and canonical transient receptor potential (TRPC) 6(-/-) mice were exposed to chronic hypoxia to induce HPH. Inhibition of Notch signaling with a γ-secretase inhibitor attenuates hypoxia-enhanced SOCE in PASMCs and hypoxia-induced increase in pulmonary arterial pressure. Our results demonstrate that hypoxia activates Notch signaling and up-regulates TRPC6 channels. Additionally, treatment with a Notch ligand can mimic hypoxic responses. Finally, inhibition of TRPC6, either pharmacologically or genetically, attenuates HPV, hypoxia-enhanced SOCE, and the development of HPH. These results demonstrate that hypoxia-induced activation of Notch signaling mediates HPV and the development of HPH via functional activation and up-regulation of TRPC6 channels. Understanding the molecular mechanisms that regulate cytosolic free Ca(2+) concentration and PASMC proliferation is critical to elucidation of the pathogenesis of HPH. Targeting Notch regulation of TRPC6 will be beneficial in the development of novel therapies for pulmonary hypertension associated with hypoxia.

Role of Kv7 channels in responses of the pulmonary circulation to hypoxia.

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K+ channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3–5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease.

Role of oxygen sensitive potassium channels in pulmonary arteries smooth muscle cells in hypoxic pulmonary vasoconstriction

Lopez Barnc于1988年采用全细胞膜片钳技术发现了大鼠颈动脉体Ⅰ型细胞膜上对低氧敏感的钾(K+)通道,称为氧敏感K+通道(O2-sensitive K+channels).在肺动脉平滑肌细胞(PASMCs)中亦存在此种离子通道.低氧时PASMCs的K+外向电流发生抑制,膜发生除极化,继而L-型电压门控Ca2+通道开放,Ca2+内流使PASMCs内[Ca2+]升高,平滑肌细胞收缩,最终导致低氧性肺血管收缩(hypoxic pulmonary vasoconstriction,HPV)。

Hypoxic pulmonary vasoconstriction: role of ion channels

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 Ca(2+) 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 Ca(2+), membrane potential, and cytoplasmic Ca(2+) in the development of acute hypoxic pulmonary vasoconstriction and chronic hypoxia-mediated pulmonary vascular remodeling.

Role of Glycolysis and Myoendothelial Gap Junctions in the Development of Hypoxic Pulmonary Vasoconstriction

1 Institute of Pharmacology and Toxicology, Academy of Medical Sciences of Ukraine, Kyiv, Ukraine. Correspondence should be addressed to A. I. Soloviev (e-mail: s.a.pharm@naverex.kiev.ua). It is well known that hypoxia causes constriction of the pulmonary artery (PA) in contrast to vasodilation in the systemic vessels. The mechanisms responsible for sensing hypoxia and initiating hypoxic pulmonary vasoconstriction (HPV) are not yet fully understood. We therefore examined the roles of glycolysis and myoendothelial gap junctions in HPV of the rat PA. The effects of glycolysis blockade on the contractile activity of the PA and aorta (A) of rats were studied under hypoxic conditions in isolated intact and denuded vascular rings, as well as in those with blocked myoendothelial electrical coupling. Hypoxia (Po 2 = 30-35 mm Hg) elicited a twophase contractile response of the intact PA consisting of transient constriction followed by dilatation. The denuded PA responded to hypoxia by dilatation. After preincubation with 20 μМ 18-glycyrrhetinic acid, a gap junction blocker, the hypoxia-induced transient constriction in intact PA rings was significantly reduced. Hypoxia elicited dilatation of intact A rings, and this effect was not changed after the removal of the endothelium. Preincubation with 18-glycyrrhetinic acid induced transient constriction in the A under hypoxic conditions. Selective blockade of glycolysis (10 μM iodoacetic acid in combination with 1 mM pyruvate) abolished hypoxic constriction in intact PA and promoted dilatation. However, selective blockade of glycolysis had no effect on the PA hypoxic responses after denudation or blockade of myoendothelial gap junctions with 18-glycyrrhetinic acid. Selective glycolysis blockade had no effect on contractile responses to hypoxia of the intact, denuded, and 18-glycyrrhetinic acidtreated A. We conclude that hypoxic constriction of the PA is an endothelium-dependent phenomenon in contrast to hypoxic dilatation of the A. It is likely that glycolysis in endothelial cells contributes, via myoendothelial gap junctions, to hypoxic pulmonary vasoconstriction and, after conduction of depolarizing electrical signals from endothelial cells to underlying smooth muscle cells, causes contraction of the latter under hypoxia.

Acute and chronic hypoxic pulmonary vasoconstriction: a central role for endothelin-1?

In the pulmonary circulation, a decrease in oxygen tension results in the development of hypoxic pulmonary vasoconstriction (HPV), although the exact mechanism by which HPV occurs remains unclear. Evidence gathered from many laboratories suggests that while pulmonary arterial smooth muscle cells (PASMCs) can sense and respond to changes in oxygen tension, full expression of HPV requires modulating influences from the endothelium. In this review, we propose a model of HPV, based on recent studies from our laboratory, in which endothelin-1 (ET-1), a vasoactive peptide released from the endothelium, plays a central role and discuss how this model may be involved in the long-term adaptation to hypoxia.

Pindolol inhibits the development of hypoxic pulmonary vasoconstriction

We examined the effects of β-adrenoceptor antagonists, propranolol and pindolol, on hypoxic pulmonary vasoconstriction using isolated, blood-perfused dog lung lobes. Pindolol markedly inhibited the development of hypoxic pulmonary vasoconstriction, whereas propranolol had no effect. The different role of the drugs on hypoxic pulmonary vasoconstriction is discussed.