Hypoxic Pulmonary Vasoconstriction Response Research Articles

Pulmonary Vascular Responses to Chronic Intermittent Hypoxia in a Guinea Pig Model of Obstructive Sleep Apnea.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

Blood Flow Heterogeneity and Oxygenation in the Lung: Effect of the Hypoxic Pulmonary Vasoconstriction Response Curve

The ability of the lung to take up oxygen can be characterized by its effective diffusing capacity, which is determined by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow. At rest, the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, but under conditions of physiological stress such as exercise, oxygen uptake may be inadequate to satisfy tissue demand if flow is very heterogeneous. We previously used a mathematical model of pulmonary oxygen uptake to examine the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity. In the model, flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a normal level of heterogeneity (CV = 1.66), we simulate flow regulation over a range of oxygen consumption from rest to maximal exercise by adjusting pulmonary flow resistance in each vessel in accordance with an HPV response curve obtained from previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each pulmonary capillary; its maximal sensitivity occurs at a stimulus oxygen tension of approximately 30 torr. The purpose of the present study was to determine whether altering the shape of the HPV response curve would result in an improvement in CV reduction. Altering the HPV by shifting the sigmoidal curve to the right by 10 or 20 torr worsened CV, extraction and total pulmonary vascular resistance (PVR). Similar detrimental results were obtained when the range of oxygen tensions over which HPV varied was expanded by a factor of two, increasing the oxygen tension at which the sensitivity of HPV to oxygen tension was maximal. On the other hand, shrinking the range of variation of the HPV curve by a factor of two neither improved nor significantly worsened the CV or extraction, and resulted in a PVR distribution similar to the case of the normal HPV curve. These results demonstrate that the observed shape of the HPV response tends to minimize heterogeneity of pulmonary flow under conditions of exercise.

No effect of patent foramen ovale on acute mountain sickness and pulmonary pressure in normobaric hypoxia.

What is the central question to this study? Is there a relationship between a patent foramen ovale and the development of acute mountain sickness and an exaggerated increase in pulmonary pressure in response to 7-10h of normobaric hypoxia? What is the main finding and its importance? Patent foramen ovale presence did not increase susceptibility to acute mountain sickness or result in an exaggerated increase in pulmonary artery systolic pressure with normobaric hypoxia. This suggests hypobaric hypoxia is integral to the increased susceptibility to acute mountain sickness previously reported in those with patent foramen ovale, and patent foramen ovale presence alone does not contribute to the hypoxic pulmonary pressor response. Acute mountain sickness (AMS) develops following rapid ascent to altitude, but its exact causes remain unknown. A patent foramen ovale (PFO) is a right-to-left intracardiac shunt present in ∼30% of the population that has been shown to increase AMS susceptibility with high altitude hypoxia. Additionally, high altitude pulmonary oedema (HAPE) is a severe type of altitude illness characterized by an exaggerated pulmonary pressure response, and there is a greater prevalence of PFO in those with a history of HAPE. However, whether hypoxia per se is causing the increased incidence of AMS in those with a PFO and whether a PFO is associated with an exaggerated increase in pulmonary pressure in those without a history of HAPE is unknown. Participants (n=36) matched for biological sex (18 female) and the presence or absence of a PFO (18 PFO+) were exposed to 7-10h of normobaric hypoxia equivalent to 4755m. Presence and severity of AMS was determined using the Lake Louise AMS scoring system. Pulmonary artery systolic pressure, cardiac output and total pulmonary resistance were measured using ultrasound. We found no significant association of PFO with incidence or severity of AMS and no association of PFO with arterial oxygen saturation. Additionally, there was no effect of a PFO on pulmonary pressure, cardiac output or total pulmonary resistance. These data suggest that hypobaric hypoxia is necessary for those with a PFO to have increased incidence of AMS and that presence of PFO is not associated with an exaggerated pulmonary pressor response.

Effects of Recombinant Human Angiotensin-Converting Enzyme 2 on Response to Acute Hypoxia and Exercise: A Randomised, Placebo-Controlled Study

IntroductionAngiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system (RAS) that has been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). Enhancing ACE2 activity using GSK2586881, a recombinant form of human ACE2, could be beneficial in diseases such as ARDS but may blunt the hypoxic pulmonary vasoconstriction (HPV) response and potentially impact systemic and tissue oxygenation. This study aimed to evaluate the effect of GSK2586881 0.8 mg/kg on HPV response in healthy adult volunteers during exercise under hypoxic conditions.MethodsIn this phase I, randomised, double-blind (sponsor open) study, GSK2586881 or placebo was administered as a single intravenous (IV) dose in a two-period crossover design. Treatment periods were separated by a washout period of 3–14 days. The primary endpoint was change from baseline in pulmonary artery systolic pressure (PASP) measured by echocardiography. Secondary endpoints included RAS peptides and oxygen saturation.ResultsSeventeen adults aged 18–40 years were randomised to treatment. There were no clinically relevant differences (defined as a reduction of ≥ 5 mmHg) in change from baseline in PASP between GSK2586881 and placebo. GSK2586881 was well tolerated, with no serious adverse events, no worsening of hypoxaemia and no evidence of immunogenicity. The study was terminated early after review of the data, which showed that the predefined success criteria had not been met. Following GSK2586881 administration, levels of the RAS peptide angiotensin II decreased while angiotensin (1-7) increased, as expected, indicating that GSK2586881 was pharmacologically active.ConclusionsA single IV dose of GSK2586881 0.8 mg/kg was well tolerated but did not impact the acute HPV response in healthy volunteers.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41030-021-00164-7.

The hypoxic pulmonary vasoconstriction: From physiology to clinical application in thoracic surgery.

More than 70 years after its original report, the hypoxic pulmonary vasoconstriction (HPV) response continues to spark scientific interest on its mechanisms and clinical implications, particularly for anesthesiologists involved in thoracic surgery. Selective airway intubation and one-lung ventilation (OLV) facilitates the surgical intervention on a collapsed lung while the HPV redirects blood flow from the “upper” non-ventilated hypoxic lung to the “dependent” ventilated lung. Therefore, by limiting intrapulmonary shunting and optimizing ventilation-to-perfusion (V/Q) ratio, the fall in arterial oxygen pressure (PaO2) is attenuated during OLV. The HPV involves a biphasic response mobilizing calcium within pulmonary vascular smooth muscles, which is activated within seconds after exposure to low alveolar oxygen pressure and that gradually disappears upon re-oxygenation. Many factors including acid-base balance, the degree of lung expansion, circulatory volemia as well as lung diseases and patient age affect HPV. Anesthetic agents, analgesics and cardiovascular medications may also interfer with HPV during the perioperative period. Since HPV represents the homeostatic mechanism for regional ventilation-to-perfusion matching and in turn, for optimal pulmonary oxygen uptake, a clear understanding of HPV is clinically relevant for all anesthesiologists.

Pannexin 1 – a novel regulator of hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia by which pulmonary blood flow is redirected from poorly ventilated areas to better aerated lung regions. Sustained HPV plays a critical role in the development of pulmonary hypertension (PH) but the exact signaling pathways underlying HPV remain incompletely defined. Recently, ATP release via Pannexin 1 (Panx1) and subsequent purinergic signaling have been linked to transient receptor potential vanlloid 4 (TRPV4) channel mediated Ca2+ signaling in systemic vasoconstriction. Here, we probed for a similar role of Panx1 in HPV and the development of PH.To test the role of Panx1, we measured HPV as increase in pulmonary artery pressure (PAP) in response to hypoxia in lungs of endothelial cell (Cdh5-CreERT2/Panx1fl/fl) and smooth muscle cell specific (SMMHC-CreERT2/Panx1fl/fl) Panx1-KO mice. Isolated perfused lungs (IPL) of C57Bl6/J and Panx1-deficient mice were ventilated with normoxic (20% O2; 5% CO2, 75% N2) or hypoxic gas (1% O2; 5% CO2, 94% N2) and PAP was recorded via a pulmonary artery catheter. To elucidate the role of Panx1 in the development of PH, C57Bl6/J as well as Panx1-KO mice were kept under hypoxic conditions (10% O2) for 5 weeks followed by measurement of right ventricular systolic pressure, echocardiography and histology.Panx1 protein was expressed in human pulmonary artery endothelial cells as well as in human pulmonary artery smooth muscle cells (hPASMCs). Genetic deletion of Panx1 in smooth muscle cells, yet not in endothelial cells reduced the HPV response in isolated mouse lungs. In lungs of C57Bl6/J mice, Panx1-inhibition by the non-specific Panx1 inhibitors spironolactone or probenecid and the Panx1 specific inhibitory peptide (10Panx1) effectively attenuated HPV. Yet, genetic deletion of Panx1 in either endothelial or smooth muscle cells did not prevent the development of PH in mice. Interestingly, ATP release in response to hypoxia was not detectable in PASMC, and ATP degradation as well as inhibition of purinergic receptors failed to affect HPV. Rather, TRPV4 antagonism and Panx1 inhibition inhibited the hypoxia-induced increase of intracellular Ca2+ concentration ([Ca2+]i) in PASMC in an additive manner, suggesting that Panx1 regulates [Ca2+]i independently of the ATP-P2Y-TRPV4 signaling axis. In line with this notion, Panx1 overexpression increased the [Ca2+]i response to hypoxia in HeLa cells. Here we identify Panx1 as novel regulator of HPV. The role of Panx1 in HPV was, however, not attributable to ATP release and downstream purinergic receptor signaling or TRPV4 activation, but may involve a direct role of Panx1 as Ca2+ channel. In contrast to its role in HPV, Panx1 does not seem to contribute to chronic hypoxic PH.

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).

Characterizing the Effect of the Hypoxic Vasoconstriction Response Curve on Blood Flow Distribution and Oxygenation in the Lung

The ability of the lung to take up oxygen can be characterized by its effective diffusing capacity, which is determined by the transport characteristics of the alveolar‐capillary membrane as well as heterogeneity of pulmonary blood flow. At rest, the healthy lung has a high degree of tolerance for pulmonary flow heterogeneity, but under conditions of physiological stress such as exercise, oxygen uptake may be inadequate to satisfy tissue demand if flow is very heterogeneous. We previously used a mathematical model of pulmonary oxygen uptake to examine the ability of hypoxic pulmonary vasoconstriction (HPV) to mitigate flow heterogeneity. In the model, flow heterogeneity is characterized by the coefficient of variation (CV) of pulmonary capillary blood flow. Assuming an initial lognormal distribution of blood flow with a normal level of heterogeneity (CV = 1.66), we simulate flow regulation over a range of oxygen consumption from rest to maximal exercise by adjusting pulmonary flow resistance in each vessel in accordance with an HPV response curve obtained from previously published experimental data. The effect of HPV on vessel flow resistance is assumed to be characterized by a sigmoidal response dependent on the capillary oxygen tension, which is approximated as the mean of the venous and arterial values in each pulmonary capillary; its maximal sensitivity occurs at a stimulus oxygen tension of approximately 30 torr. The purpose of the present study was to determine whether altering the shape of the HPV response curve would result in an improvement in CV reduction. Altering the HPV by shifting the sigmoidal curve to the right by 10 or 20 torr worsened CV, extraction and total pulmonary vascular resistance (PVR). Similar detrimental results were obtained when the range of oxygen tensions over which HPV varied was expanded by a factor of two, increasing the oxygen tension at which the sensitivity of HPV to oxygen tension was maximal. On the other hand, shrinking the range of variation of the HPV curve by a factor of two neither improved nor significantly worsened the CV or extraction, and resulted in a PVR distribution similar to the case of the normal HPV curve. These results demonstrate that the observed shape of the HPV response tends to minimize heterogeneity of pulmonary flow under conditions of exercise.Support or Funding InformationSupported by NIH U01 HL133362.

TRPC6 deficiency or feeding a high fat diet impairs ventilatory responses to hypercapnia

Transient receptor potential cation channel C (TRPC) is essential for hypoxic pulmonary vasoconstriction response and alveolar gas exchange. We previously showed that whole body TRCP6 deficient (TRPC6 KO) mice are obese and resistant to the anorexic effects of leptin, a hormone that modulates ventilatory control. In the present study we investigated ventilatory responses to hypercapnia (7% CO2) in male and female 22‐week‐old TRPC6 KO and B6/129 control mice fed normal or high fat diet (HFD) since weaning (n=5 per group/sex/diet). Pulmonary ventilation (VE), tidal volume (VT) and respiratory frequency (FR) were measured using the plethysmography method. TRPC6 KO mice were heavier than control mice when fed normal diet (46.2±1.9 vs. 36.6±2.2 g in males and 34.0±1.4 vs. 26.9±1.3 g in females). However, when fed a HFD, male and female TRPC6 KO and B6/129 mice had similar body weight (43.6±0.4 vs. 47.5±1.4 g and 40.1±0.6 vs. 40.7±2.5 g, respectively). Compared to B6/129 controls male and female TRPC6 KO mice fed normal diet had similar VE (1817± 233 vs. 2139±135 and 2146± 404 vs. 2943±421 ml/min/kg) and VT (10.9±0.6 vs. 9.9±0.6 and 17.0±3.4 vs. 14.6±0.8 ml/kg), but lower FR (130±9 vs. 217±14 and 127±5 vs. 201±26 breaths/min) at room air. During hypercapnia, only male TRPC6 KO mice exhibited lower VE (3631± 493 vs. 6003±698 ml/min/kg), which was due to lower FR (235 ±16 vs. 305±19 breaths/min) and VT (15.3±1.0 vs. 19.5±1.4 ml/kg) responses to 7% CO2. Although female TRPC6 KO mice also showed lower FR to hypercapnia compared to B6/129 controls (242±6 vs. 313±22 breaths/min) they exhibited higher VT (28.4±3.0 vs. 25.8±2.0 ml/kg), thus resulting in similarly increased VE (6914±847 vs. 8119±956 ml/min/kg). Male and female B6/129 mice fed a HFD had significantly reduced VE responses to 7% CO2 (4020± 332 vs. 6003±698 and 5140± 194 vs. 8119±956 ml/min/kg, respectively) that were mainly caused by reduced VT (14.4±1.3 vs. 19.5±1.4 and 18.8±0.6 vs. 25.8±2.0 ml/kg). No further reduction in in ventilatory responses to hypercapnia were observed in male or female TPRC6 KO mice fed a HFD. These results suggest that TRPC6 plays an important role in ventilatory responses to hypercapnia, albeit more profound in males than females, and that HFD significantly reduces ventilatory responses to hypercapnia in both male and female control mice, but not in TRPC6 KO mice. The mechanisms involved in the reduced ventilatory responses are still unclear but may involve reduced sensitivity to leptin evoked by HFD or TRPC6 deficiency.Support or Funding InformationNIDDK 1RO1121411, NHLBI‐PO1HL51971, NIGMS P20GM104357 and U54GM115428

Human Genetic Adaptation to High Altitude: Evidence from the Andes.

Whether Andean populations are genetically adapted to high altitudes has long been of interest. Initial studies focused on physiological changes in the O2 transport system that occur with acclimatization in newcomers and their comparison with those of long-resident Andeans. These as well as more recent studies indicate that Andeans have somewhat larger lung volumes, narrower alveolar to arterial O2 gradients, slightly less hypoxic pulmonary vasoconstrictor response, greater uterine artery blood flow during pregnancy, and increased cardiac O2 utilization, which overall suggests greater efficiency of O2 transfer and utilization. More recent single nucleotide polymorphism and whole-genome sequencing studies indicate that multiple gene regions have undergone recent positive selection in Andeans. These include genes involved in the regulation of vascular control, metabolic hemostasis, and erythropoiesis. However, fundamental questions remain regarding the functional links between these adaptive genomic signals and the unique physiological attributes of highland Andeans. Well-designed physiological and genome association studies are needed to address such questions. It will be especially important to incorporate the role of epigenetic processes (i.e., non-sequence-based features of the genome) that are vital for transcriptional responses to hypoxia and are potentially heritable across generations. In short, further exploration of the interaction among genetic, epigenetic, and environmental factors in shaping patterns of adaptation to high altitude promises to improve the understanding of the mechanisms underlying human adaptive potential and clarify its implications for human health.

Dasatinib-induced pulmonary arterial hypertension.

Drug-induced (group 1) pulmonary hypertension (PH) is an important subgroup of PH involving dasatinib as a likely related agent, which is a second-generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukaemia (CML). The mechanism of dasatinib-induced pulmonary arterial hypertension (PAH) is unclear. However, the occurrence of PAH with late onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac aetiology. Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases. Therefore, Src inhibition was thought to play a role in the development of dasatinib-induced PAH. However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism. Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies. Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment.

The role of nitric oxide in the cardiopulmonary response to hypoxia in highland and lowland newborn llamas.

Perinatal hypoxia causes pulmonary hypertension in neonates, including humans. However, in species adapted to hypoxia, such as the llama, there is protection against pulmonary hypertension. Nitric oxide (NO) is a vasodilatator with an established role in the cardiopulmonary system of many species, but its function in the hypoxic pulmonary vasoconstrictor response in the newborn llama is unknown. Therefore, we studied the role of NO in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. We show that high- compared to lowland newborn llamas have a reduced pulmonary vasoconstrictor response to acute hypoxia. Protection against excessive pulmonary vasoconstriction in the highland llama is mediated via enhancement of NO pathways, including increased MYPT1 and reduced ROCK expression as well as Ca2+ desensitization. Blunting of pulmonary hypertensive responses to hypoxia through enhanced NO pathways may be an adaptive mechanism to withstand life at high altitude in the newborn llama. Llamas are born in the Alto Andino with protection against pulmonary hypertension. The physiology underlying protection against pulmonary vasoconstrictor responses to acute hypoxia in highland species is unknown. We determined the role of nitric oxide (NO) in the cardiopulmonary responses to acute hypoxia in high- and lowland newborn llamas. The cardiopulmonary function of newborn llamas born at low (580m) or high altitude (3600m) was studied under acute hypoxia, with and without NO blockade. In pulmonary arteries, we measured the reactivity to potassium and sodium nitroprusside (SNP), and in lung we determined the content of cGMP and the expression of the NO-related proteins: BKCa, PDE5, PSer92-PDE5, PKG-1, ROCK1 and 2, MYPT1, PSer695-MYPT1, PThr696-MYPT1, MLC20 and PSer19-MLC20. Pulmonary vascular remodelling was evaluated by morphometry and based on α-actin expression. High- compared to lowland newborn llamas showed lower in vivo pulmonary arterial pressor responses to acute hypoxia. This protection involved enhanced NO function, as NO blockade reverted the effect and the pulmonary arterial dilatator response to SNP was significantly enhanced in highland neonates. The pulmonary expression of ROCK2 and the phosphorylation of MLC20 were lower in high-altitude llamas. Conversely, MYPT1 was up-regulated whilst PSer695-MYPT1 and PThr695-MYPT1 did not change. Enhanced NO-dependent mechanisms were insufficient to prevent pulmonary arterial remodelling. Combined, the data strongly support that in the highland newborn llama reduced ROCK, increased MYPT1 expression and Ca2+ desensitization in pulmonary tissue allow an enhanced NO biology to limit hypoxic pulmonary constrictor responses. Blunting of hypoxic pulmonary hypertensive responses may be an adaptive mechanism to life at high altitude.

Mitochondrial Complex I Dysfunction and Peripheral Chemoreflex Sensitivity in a FASTK-Deficient Mice Model.

The molecular mechanisms underlying O2-sensing by carotid body (CB) chemoreceptors remain undetermined. Mitochondria have been implicated, due to the sensitivity of CB response to electron transport chain (ETC) blockers. ETC is one of the major sources of reactive oxygen species, proposed as mediators in oxygen sensing. Fas-activated serine/threonine phosphoprotein is a sensor of mitochondrial stress that modulates protein translation to promote survival of cells exposed to adverse conditions. A translational variant of Fas-activated serine/threonine kinase (FASTK) is required for the biogenesis of ND6 mRNA, the mitochondrial encoded subunit 6 of the NADH dehydrogenase complex (Complex I). Ablating FASTK expression reduced Complex I activity in vivo by about 50%. We have tested the hypothesis of Complex I participation in O2-sensing structures by studying the effect of hypoxia in FASTK-/- knockout mice. Ventilatory response to acute hypoxia and hypercapnia tests showed similar sensitivity and CB catecholaminergic activity in knockout and wild type mice; hypoxic pulmonary vasoconstriction response also was similar. Pulmonary artery contractility in vitro, using small vessel myography, showed a significantly decreased relaxation to rotenone in knockout mice pre-constricted vessels with PGF2α. In conclusion, FASTK-/- knockout mice maintain respiratory chemoreflex under hypoxia and hypercapnia stress suggesting that completely functional Complex I ND6 protein is not required for these responses.

A Decrease in Hypoxic Pulmonary Vasoconstriction Correlates With Increased Inflammation During Extended Normothermic Ex Vivo Lung Perfusion.

Normothermic ex vivo lung perfusion (EVLP) is an evolving technology to evaluate function of donor lungs to determine suitability for transplantation. We hypothesize that hypoxic pulmonary vasoconstriction (HPV) during EVLP will provide a more sensitive parameter of lung function to determine donor lung quality for lung transplantation. Eight porcine lungs were procured, and subsequently underwent EVLP with autologous blood and STEEN solution for 10 h. Standard physiologic parameters including dynamic compliance, peak airway pressure, and pulmonary vascular resistance (PVR) remained stable (P = 0.055), mean oxygenation (PO2 /FiO2 ) was 400 ± 18 mm Hg on average throughout perfusion. Response to hypoxia resulted in a robust increase in PVR (ΔPVR) up to 4 h of perfusion, however the HPV response then blunted beyond T6 (P < 0.01). The decrease in HPV response inversely correlated to cytokine concentrations of Interleukin-6 and tumor necrosis factor-α (P < 0.01). Despite acceptable lung oxygenation and standard physiologic parameters during 10 h of EVLP, there is a subclinical deterioration of lung function. HPV challenges can be performed during EVLP as a simple and more sensitive index of pulmonary vascular reactivity.

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Therapeutic Role of Ambrisentan for the Treatment of Hypoxic Pulmonary Vasoconstriction: Impact of Intrapulmonary Delivery

Hypoxic pulmonary vasoconstriction (HPV) results in robust increases in pulmonary artery pressures (PAP), which underlie the development of pulmonary hypertension (PH), and potentially edema, in those that travel to or work at altitude. Endothelin‐1 receptor (ET‐1) antagonists are currently given orally to treat PH, however intrapulmonary delivery of this therapeutic may provide acute relief of the HPV response at a lower dose and thus could ameliorate the functional impairments caused by PH whilst minimizing the amount of drug required. Despite this potential, the efficacy of intrapulmonary ET‐1 antagonist therapy to treat hypoxia induced PH has yet to be determined. We tested the hypothesis that intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan would attenuate an HPV mediated increase in PAP when compared to a saline control. Adult male Sprague‐Dawley rats were randomized into three groups to receive aerosolized saline (Saline, n=8), a low dose (ALD, 1 mg/kg, n=8) or high dose (AHD, 5 mg/kg, n=8) of Ambrisentan (administered via a microinhaler) following the induction of HPV (via 13% inspired O2, simulating ~4000m). PAP were monitored continuously throughout the procedure via indwelling catheters. Pre‐hypoxia PAP values were not different between groups (Saline: 18 ± 1, ALD 19 ± 1, AHD: 17 ± 1 mmHg, P&gt;0.05). Following an initial hypoxia induced increase in PAP (Saline: 37 ± 1, ALD: 30 ± 2, AHD: 33 ± 2 mmHg, P&lt;0.05 vs. pre‐hypoxia for all) intrapulmonary Ambrisentan reduced significantly PAP when compared to Saline (Saline: 34 ± 1, ALD: 23 ± 1, AHD, 23 ±1 mmHg, P&lt;0.05) with no significant differences between ALD and AHD (P&gt;0.05). Intrapulmonary delivery of the ET‐1 receptor antagonist Ambrisentan reduced significantly the increase in PAP following exposure to hypoxia with no significant differences between low and high doses. These results suggest that intrapulmonary delivery of Ambrisentan, at a dose approximating 1/5th of that given orally, may be an effective therapeutic for the treatment of hypoxia induced PH. Given the life threatening complications and impaired work capacity associated with PH and high altitude pulmonary edema (HAPE), individuals traveling to or working at altitude (i.e. military and mining personnel, mountain athletes) as well as those suffering from pathologically induced PH may benefit from acute intrapulmonary delivery of Ambrisentan.Support or Funding InformationONR# N00014‐14‐1‐0699DARPA # N66001‐10‐C‐2134

Hypoxic pulmonary vasoconstriction and vascular contractility in monocrotaline-induced pulmonary arterial hypertensive rats.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vascular remodeling of pulmonary arteries (PAs) and increased vascular resistance in the lung. Monocrotaline (MCT), a toxic alkaloid, is widely used for developing rat models of PAH caused by injury to pulmonary endothelial cells; however, characteristics of vascular functions in MCT-induced PAH vary and are not fully understood. Here, we investigated hypoxic pulmonary vasoconstriction (HPV) responses and effects of various vasoconstrictors with isolated/perfused lungs of MCT-induced PAH (PAH-MCT) rats. Using hematoxylin and eosin staining, we confirmed vascular remodeling (i.e., medial thickening of PA) and right ventricle hypertrophy in PAH-MCT rats. The basal pulmonary arterial pressure (PAP) and PAP increase by a raised flow rate (40 mL/min) were higher in the PAH-MCT than in the control rats. In addition, both high K+ (40 mM KCl)- and angiotensin II-induced PAP increases were higher in the PAH-MCT than in the control rats. Surprisingly, application of a nitric oxide synthase inhibitor, L-NG-Nitroarginine methyl ester (L-NAME), induced a marked PAP increase in the PAH-MCT rats, suggesting that endothelial functions were recovered in the three-week PAH-MCT rats. In addition, the medial thickening of the PA was similar to that in chronic hypoxia-induced PAH (PAH-CH) rats. However, the HPV response (i.e., PAP increased by acute hypoxia) was not affected in the MCT rats, whereas HPV disappeared in the PAH-CH rats. These results showed that vascular contractility and HPV remain robust in the MCT-induced PAH rat model with vascular remodeling.

Illness at high altitudes.

Illness at high altitudes.

Hypoxic pulmonary vasoconstriction as a contributor to response in acute pulmonary embolism.

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive response unique to the lung whereby blood flow is diverted away from areas of low alveolar oxygen to improve ventilation-perfusion matching and resultant gas exchange. Some previous experimental studies have suggested that the HPV response to hypoxia is blunted in acute pulmonary embolism (APE), while others have concluded that HPV contributes to elevated pulmonary blood pressures in APE. To understand these contradictory observations, we have used a structure-based computational model of integrated lung function in 10 subjects to study the impact of HPV on pulmonary hemodynamics and gas exchange in the presence of regional arterial occlusion. The integrated model includes an experimentally-derived model for HPV. Its function is validated against measurements of pulmonary vascular resistance in normal subjects at four levels of inspired oxygen. Our results show that the apparently disparate observations of previous studies can be explained within a single model: the model predicts that HPV increases mean pulmonary artery pressure in APE (by 8.2±7.0% in these subjects), and concurrently shows a reduction in response to hypoxia in the subjects who have high levels of occlusion and therefore maximal HPV in normoxia.

VEGF189Expression Is Highly Related to Adaptation of the Plateau Pika (Ochotona curzoniae) Inhabiting High Altitudes

The plateau pika (Ochotona curzonia) has adapted to high-altitude hypoxia during evolution. Higher microvessel density in specific tissues and a blunted hypoxic pulmonary vasoconstriction response are the critical components of this adaptation. VEGF, vascular endothelial growth factor, has proved to be a key regulator of angiogenesis in response to tissue hypoxia and to play an important role in vascular vasodilation. However, the role of VEGF in adaptation to high-altitude hypoxia in the plateau pika remains unknown. In this study, we cloned cDNAs for VEGF165 and VEGF189 and examined their expression in pikas inhabiting altitudes of 3200 and 4750 m. Phylogenetic analysis reveals that pika VEGF165 and VEGF189 are evolutionarily conserved. Real-time PCR analysis demonstrates that VEGF165 and VEGF189 display tissue and altitude-specific expression patterns. Interestingly, we found that the levels of VEGF189 mRNA are significantly higher than those of VEGF165 in the brain and muscle tissues of the pika, which is different from what was previously observed in sea-level mammals. VEGF189 mRNA levels in brain, muscle, and lung of the pika increased with increased habitat altitude, whereas VEGF165 shows less change. Our study suggests an important role for VEGF189 in adaptation to hypoxia by the plateau pika in the high-altitude environment.