How does hypoxia cause pulmonary hypertension

The symptoms of pulmonary hypoxic hypertension are similar to the symptoms of other types of pulmonary hypertension and include shortness of breath dyspnea , fatigue, dizziness or fainting spells, chest pain, swelling of the legs and ankles edema , blue-colored lips and skin cyanosis , and irregular heartbeat. Multiple medical tests will be carried out to diagnose this and other forms of pulmonary hypertension. The key tests for a diagnosis of pulmonary hypoxic hypertension will involve:.

There are no therapies specifically for pulmonary hypoxic hypertension. Treatment is focused mainly on the underlying cause of the condition.

Alternatively, general pulmonary hypertension therapies can be used. These include anticoagulants, to prevent blood clots, and diuretics, to reduce swelling. This raises the intriguing possibility that the molecular drivers of these hypoxic processes could be targeted to modify pulmonary vascular remodeling in other contexts. In this review, we outline the history of research into PH and hypoxia, before discussing recent advances in our understanding of this relationship at the molecular level, focussing on the role of the oxygen-sensing transcription factors, hypoxia inducible factors HIFs.

Emerging links between HIF and vascular remodeling highlight the potential utility in inhibiting this pathway in pulmonary hypertension and raise possible risks of activating this pathway using HIF-stabilizing medications. Pulmonary hypertension PH is a feature of several distinct clinical phenotypes which, by differing means, result in increased pressure within the pulmonary vasculature.

Despite some advancements in treatment over recent years 1 , most forms of PH are progressive and life-limiting. Alongside parenchymal changes, two key pathological process, pulmonary vascular remodeling and vasoconstriction, contribute to PH in this group of patients but treatment with pulmonary vasodilators has, to date, been disappointing.

While pathologic mechanisms might vary depending on the underlying disease or phenotype, a better understanding of the defining component of Group III disorders, hypoxia, may help provide new targets for therapies.

A causal relationship between hypoxia and PH is well established; hypoxia is frequently used to both precipitate PH in animal models 5 and to induce aberrant cell phenotypes in vitro 6. These approaches have greatly improved our understanding of the underlying physiological mechanisms that drive the pathology. In humans, compelling evidence of the effects of hypoxia on pulmonary vascular tone and remodeling derives from studies performed at altitude, where the inherent reduction in barometric pressure results in hypobaric hypoxia.

This approach is advantageous for evaluation of the effects of hypoxia on the pulmonary vasculature in relative isolation, without the complicating factors of disease. In this review, we outline the historical context of research into PH and hypoxia and discuss emerging molecular mechanisms for this relationship.

We focus on the role of the oxygen-sensing transcription factors, hypoxia inducible factors HIFs , and links between HIFs and vascular remodeling. Before embarking on this review, it is important to consider the definitions of PH used within this manuscript and others.

Notably, at the recent 6th WSPH, the upper limit of normal for mPAP was set at 20 mmHg, argued in part due to emerging evidence of poorer survival in patients with mPAPs of 21—24 mmHg and in part based on the distribution of values in healthy population data 8.

Pre-capillary hemodynamics that meet the above definition, are not uncommon in patients with lung disease 4 , 9 , but the prevalence of increased PVR in healthy individuals who are hypoxic without lung disease, for example altitude residents and those with sleep apnoea, is less clear and will be discussed later However, the etiology of PH remained elusive at this time and was wrongly attributed to syphilis for many years 12 , Whilst the British cardiologist Oscar Brenner eventually disproved this link in , he could not provide an explanation for pulmonary vascular changes coinciding with RVH It was only with the advent of right heart catheterization in the mid-twentieth century that these observations were intrinsically linked by raised pulmonary artery pressure PAP.

Despite extensive use in animals in the early twentieth century, cardiac catheterization in humans was widely considered unsafe until Werner Forssman's gallant self-catheterization of his right heart in 15 , Whilst this act of bravery was initially poorly received and widely ignored by the medical community, American physicians Dickinson Richards and Andrew Cournard would recognize the importance of Forssman's work in the s.

Their pioneering research characterized mPAP in cardiac and pulmonary diseases for the first time, a feat for which they were awarded a Nobel Prize, together with Forssman, in 17 , Further work in the s began to establish the clinical and pathological features of PH.

In , one of the first detailed descriptions of the haemodynamic profiles of the disease was provided by David Dresdale who also observed cyanosis, orthopnoea and haemoptysis amongst patients with idiopathic PH. Additionally, an extensive characterization of histological changes in PH was described by Donald Heath who, in collaboration with William Whitaker, first detailed extensive thickening of the pulmonary arterial wall associated with fibrosis in , amongst individuals with congenital heart disease, mitral stenosis and idiopathic PH 21 , Heath and Jesse Edwards subsequently produced a detailed histological classification system correlated to PH severity in Eisenmenger's syndrome, which ranged from early vascular medial hypertrophy in mild PH to late intimal fibrosis in severe disease Despite elevated PAP being first associated with ventilatory failure in 24 , a causal relationship between hypoxia and PH only became established in when von Euler and colleagues demonstrated increased mPAP on exposing cats to both hypoxia and hypercapnia 25 ; in , Dresdale reported similar findings in humans These reports constituted the first measurements of pulmonary arteriole constriction to hypoxia, or hypoxic pulmonary vasoconstriction HPV , a phenotype which contrasts the vasodilating properties of hypoxia on the systemic circulation At the time, von Euler correctly hypothesized that this physiological response is beneficial in order to shunt blood from areas of regional lung hypoxia that stems from reduced ventilation, thus maintaining blood oxygenation a concept now termed ventilation-perfusion matching.

However, the adverse effects of this response in the context of more global alveolar hypoxia soon became apparent, particularly in relation to high-altitude pulmonary oedema HAPE. Whilst a syndrome of cough, blood-stained sputum and severe breathlessness was previously recognized in high altitude sojourners, Hurtado was the first to attribute this to pulmonary oedema in Hultgren et al.

Further work from this group, along with others 32 , identified a predisposition to pulmonary oedema amongst five individuals with mPAPs of Despite the early identification of PH as a factor in the pathogenesis of HAPE, how this results in oedema formation remains unclear. Hultgren proposed that because HPV is heterogeneous, areas of the lung are over-perfused leading to pulmonary capillary stress failure in HAPE Other factors in HAPE pathogenesis include impaired nitric oxide NO biosynthesis and reduced alveolar fluid reabsorption, as reviewed here 37 , Concurrently, research began to investigate the effects of chronic hypoxia on the pulmonary vasculature of high-altitude populations.

In the s, Rue Jensen first identified right ventricular dilatation and failure co-existing with brisket disease amongst the high-altitude cattle populations in Colorado 39 , with further work with Grover, Reeves and Will identifying a positive correlation between the severity of RVH and the degree of raised PAP Further breeding experiments led by Grover and Reeves suggested an autosomal dominant inheritance of HAPH among these cattle 41 , Interestingly, similar findings were documented by Anand et al.

While no measurements were made at altitude, shortly after return to sea level right heart catheter studies on these patients provided evidence of mild pre-capillary pulmonary hypertension, with mPAP and PVR measured as Elevated PAP in human populations at high altitude was first reported in by Canepa in one of the first reports of human right heart catheterization in Peruvians from Morochoca 4, m , recorded as 25 range 18—29 mmHg amongst 7 highlanders and 34 and 35 mmHg amongst two chronic mountain sickness patients; however, these findings were initially attributed to polycythaemia, abnormal ventilation and increased cardiac output Further weight to this hypothesis was added by Jensen and Alexander, who later demonstrated a linear relationship between medial hypertrophy of the pulmonary arteries and PAP amongst cattle Complementing this finding, the Indian soldiers studied by Anand et al.

While the above studies in healthy individuals imply that elevated pulmonary artery pressures are found ubiquitously at altitude, whether the magnitude of elevation in healthy altitude residents reaches that which would define pre-capillary PH remains unclear. A recent meta-analysis by Soria et al. Furthermore, PVR is seldom reported and a notable limitation of reported PVRs among historical catheterization studies at altitude, is the lack of correction for hematocrit.

Resistance to blood flow is dependent upon viscosity as well as vessel dimensions [reviewed by Vanderpool and Naeije 53 ], with equations describing the relationship derived from isolated perfused lung experiments involving alterations in haematocrit Thus, reporting of haematocrit is important in determining true PVR 53 , 55 and may lead to false assumptions regarding the extent of vascular remodeling in healthy individuals following hypoxic exposure.

Nonetheless, similar to observations in patients with lung disease, there is a sub-population of altitude residents who develop more severe PH.

This definition allowed discrimination between HAPH and chronic mountain sickness CMS , in which there is excessive erythrocytosis 57 , Despite aforementioned epidemiological studies indicating the rarity of HAPH by the above definition amongst high altitude dwellers 10 , the study of such individuals may provide important insights into molecular pathways that drive vasoconstrictive and remodeling processes in both hypoxic PH and, potentially, other forms of PAH.

However, it could be argued that a revision of the current definition of HAPH, to include haematocrit-corrected PVR, would facilitate this research. Following these results in both humans and cattle, Donald Heath became interested in inter-species variability in the pulmonary vasculature of high-altitude populations. Heath traveled to Cerro de Pasco, Peru 4, m alongside Peter Harris in , in what became the first of many high-altitude research expeditions dedicated to PH research.

A descriptive overview of this work is provided by one of this article's authors in Box 1. In , Heath published their research in llamas Lama glama demonstrating a lack of pulmonary arteriole muscularisation or RVH at altitude, contrasting previous findings in humans and cattle Bos taurus A similarly thin walled pulmonary vasculature was also identified in the Himalayan yak Bos grunniens 60 , indicating a role of natural selection in the loss of the thick-walled, reactive pulmonary arteries typically characteristic of the Bos genus.

The recognition of the different biological classes of man and mammals at high altitude is best illustrated by taking a mental stroll around the streets and surrounding countryside of any small town in the high Andes.

The studies undertaken demonstrated that there was no single stereotypical man or mammal at high altitude. Cerro de Pasco is a mining community with a population of 70, people, situated at an attitude of m in the central Andes of Peru. In the streets will be a number of lowlanders who may have arrived at high altitude in a matter of hours from Lima on the coast. These symptoms are the consequence of hypobaric hypoxia and may be regarded as the physiological components of early acclimatization.

In contrast, most people are native Quechua Indians born and bred in the high Andes. These descendants of the Inca people have very characteristic physical features of skin color with deeply polycythaemic and suffused conjunctiva and lips. Many will have a capacious chest which looks prominent and out of proportion to their short and stocky physique. These native highlanders lead normal busy lives at high altitude.

They participate in vigorous games of football at altitudes exceeding the summit of the Matterhorn in the Swiss Alps. Living on the pastures surrounding Cerro de Pasco are examples of indigenous mountain animals such as the llama, alpaca, vicuna and guanaco. These animals have been living on the Andean altiplano for many thousands of years. One cannot help but be impressed by the vigor and activity of these animals in an atmosphere characterized by severe hypobaric hypoxia.

An interesting biological issue arises when species from within the same genus interbreed; one such example is the interbreeding of cattle giving rise to species such as the dzo cow x yak and stol dzo x bull In , work from Peter Harris' group identified that protection from PH correlated with the degree of yak heritage; whilst dzos and yaks demonstrated minimal PH, half of the stols had significantly raised PAPs similar to that of cattle 62 , indicating a degree of inheritance.

These observations lend support to the concept that animals indigenous to high altitude have become genetically adapted to their hypoxic environment, vs. While the evidence above clearly illustrates connections between hypoxic exposure and pulmonary hypertension, the underlying genetic, molecular and cellular mechanisms that regulate these phenotypes remain unclear and in part, controversial. Nonetheless, basic science work over the last 25 years has advanced our understanding of common pathways that govern both adaptation to altitude and hypoxia-induced PH.

Reviewed extensively elsewhere 63 — 65 , pulmonary vasoconstriction in acute hypoxia comprises at least two phases involving distinct mechanisms.

Initially, changes in redox status within smooth muscle cell mitochondria mediate alterations in potassium and voltage-gated calcium channel flux, promoting contraction Such neovascularization may provide a beneficial adaptation by increasing the area of the gas exchange membrane. These novel structural findings are supported by recent reports that inhibitors of the RhoA pathway can acutely reduce pulmonary vascular resistance in chronically hypoxic lungs to near normal values, demonstrating that structural changes are not the dominant mechanisms underling hypoxic pulmonary hypertension.

Chronic hypercapnia inhibits the development of hypoxic pulmonary hypertension, pulmonary vascular remodelling and hypoxia-induced angiogenesis. CP is a rare autosomal recessive condition that is endemic to the population in Chuvashia, Russia and in the island of Ischia, Italy [ 46 , 48 ].

In addition, these patients are highly susceptible to both arterial and venous thrombosis and can develop mild to severe PH [ 45 — 49 ]. Zinc, an essential dietary element, plays an important cytoprotective role for the lung by sheltering the pulmonary epithelium from extrinsic activation of apoptotic pathways following acute lung injury [ 52 ]. Zinc transporters are responsible for zinc cellular uptake and homeostasis [ 53 ]. A recent linkage analysis study that compared a PH-resistant rat strain, Fisher F , with the Wistar Kyoto WKY strain identified the gene Slc39a12 , which encodes the ZIP12 zinc transporter, as a major regulator of hypoxia-induced pulmonary vascular remodelling [ 53 ].

In the F strain, this gene lacks a crucial thymidine, which leads to a frameshift mutation in exon 11 and renders translation of the protein redundant. ZIP12 is normally expressed in endothelial, interstitial and VSMCs, but its expression increases in remodelled pulmonary vessels following hypoxia-induced PH [ 53 ].

Zinc-binding motifs have been considered as potential PH drug-therapeutic targets with phosphodiesterase type 5 PDE5 and histone deacetylases as examples [ 54 , 55 ]. Zinc is a structural component of a number of intracellular enzymes, transcription factors, other proteins and cofactors and is a putative drug target for PH.

Hypoxic stimulation of a variety of human cell types has shown induction of more than 90 miRNAs [ 56 ], with altered expression of some of these miRNAs involved in VSMC remodelling and endothelial cell dysfunction in PH [ 57 ]. MiR has been shown to be downregulated in VSMCs of patients suffering from PH, as well as in mouse models of the disease [ 58 , 59 ]. The degree of miR suppression has been found to be inversely proportional to the degree of pulmonary artery resistance and pressure, while compensating for the loss of miR through nebulisation in PH patients has been shown to reverse the VSMC proliferative and anti-apoptotic phenotype [ 59 ].

MiR expression has been found to be upregulated in both pulmonary VSMC and endothelial cells during hypoxic conditions [ 61 , 65 ]. Treatment of mice with anti-miR during hypoxia showed an improvement in distal pulmonary artery muscularisation [ 69 ]. However, miR has also been shown to have a protective effect during PH [ 61 ]. Specifically, miR deletion showed exaggerated pulmonary vascular remodelling, whereas in mice overexpressing miR, these disease-associated phenotypes were abolished [ 61 ].

So far, PH animal models have helped greatly in these studies, but the exact role and balance for each of these miRNAs in human PH have not been fully elucidated.

Mechanistic target of rapamycin mTOR is a cellular hub that controls growth factor signalling and nutrient sensing to regulate cell growth, proliferation, metabolism and survival [ 71 ]. Aberrant mTOR activity has a well-characterised role in promoting proliferative diseases including cancer and smooth muscle cell pathologies [ 71 ]. Accordingly, mTOR inhibitors are widely used in drug-eluting stents to prevent restenosis.

As such, rapamycin analogues may have therapeutic potential for treating PH. The relationship between hypoxic conditions and mTOR is complex and depends, in part, on cellular context. Many cell types respond to prolonged periods of hypoxia by inactivating energy-intensive processes such as protein synthesis and proliferation, and accordingly mTOR is downregulated [ 82 ]. By contrast, the vasculature responds to long-term hypoxia by promoting new blood vessel growth—angiogenesis, which in turn, restores O 2 to deprived tissues.

Hypoxic stress is a key driving force in the vascular remodelling observed in pulmonary hypertension, and HIFs activate pulmonary artery endothelial and smooth muscle cell proliferation, which is mediated by both mTORC1 and mTORC2 [ 83 — 85 ].