Journal of Hypertension and Cardiology

Current Issue Volume No: 1 Issue No: 3

Open Access Available online freely Peer Reviewed Citation

Hypertension in Hypoxia

Sheetal Chawla 1,   Rashi Singhal 1,   Prasenjit Guchhait 1  

1UNESCO Regional Centre for Biotechnology, Delhi NCR, India.

Author Contributions
Received 23 Dec 2013; Accepted 14 Jul 2014; Published 08 Oct 2014;

Copyright ©  2014  Sheetal Chawla, et al

License
Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing interests

The authors have declared that no competing interests exist.

Citation:

Sheetal Chawla, Rashi Singhal, Prasenjit Guchhait (2014) Hypertension in Hypoxia. - 1(3):1-16. https://doi.org/10.14302/issn.2329-9487.jhc-14-edt3

Download as RIS, BibTeX, Text (Include abstract )

DOI 10.14302/issn.2329-9487.jhc-14-edt3

Introduction

Hypertension is a pathophysiological condition, when arterial blood pressure is elevated. The heart works harder to overcome the increased systemic pressure in order to maintain blood flow to cells and tissues. Over time, the additional strain on the heart and arteries slowly leads to deadly sequelae such as congestive heart failure, myocardial infarction, pulmonary embolism, cerebral aneurysm and kidney failure1. Primary hypertension is the most frequent, accounts about 90-95% incidences. It is associated with many factors such as sedentary lifestyle, stress, tobacco smoking, diabetes, high salt intake, potassium deficiency and sodium sensitivity, obesity, alcohol intake and vitamin D deficiency2, 3. Other hand, secondary hypertension is less frequent, and is linked to mainly dysfunctions and disorders associated with central nervous system, kidneys, lungs, vascular and endocrine system4.

This review focuses on altitude-associated hypertension in the tourists, trekkers, and mountaineers who visit high altitude and normally reside near sea level. The acute physiological adjustments and early acclimatization that occur in the cardiovascular and pulmonary systems, ensures the oxygen delivery to the cells and tissues despite a significant reduction in the partial oxygen pressure. The review discusses also the high altitude tolerance and adaptations of the mountain dwellers living for generations. The review describes the pathogenesis of hypertension in general and molecular mechanisms of pulmonary hypertensions associated with high altitude hypoxia and different disease conditions.

Pathophysiology of Hypertension

Hypertension is a common health problem, affecting about 33% populations worldwide associated with significant morbidity and mortality5. Hypertension is a chronic elevation of blood pressure (BP) that, in the long-term, causes organ dysfunction and damage. The absolute risk for hypertension even further increases in disease condition such as cardiovascular disease (CVD) when elevated BP coexists with other CVD risk factors, such as diabetes and dyslipidemia. The pathophysiology of hypertension involves a number of mechanisms that interact in complex fashion to influence BP and their derangement further plays a crucial role in developing a severe form. Many factors contribute to the raised blood pressure in hypertensive patients, including cardiac output and systemic vascular resistance, renin-angiotensin-aldosterone system, sympathetic nervous system, endothelial dysfunctions, and obesity and insulin resistance.

Cardiac Output and Vascular Resistance:

A balance between the cardiac output and peripheral vascular resistance normally maintains the BP. As the consequence a series of cardiovascular adjustments take place to increase blood volume during early primary hypertension. Firstly, as the result of increased blood volume circulating through the heart, cardiac output increases. As the systemic arteries sense the increase in blood volume, arterial constriction occurs, which finally leads to an increase in total peripheral resistance during hypertension.

At borderline hypertension BP is elevated due to raised cardiac output and not of increased vascular resistance, which is related to sympathetic hyperactivity. Other hand, the patients with essential hypertension show a normal cardiac output with an elevated peripheral resistance. This subsequent increase in peripheral arteriolar resistance might therefore prevent the elevated pressure being transmitted to the capillaries where it would substantially affect homeostasis. The peripheral resistance is determined basically by smooth muscle cells of arterioles, not by large arteries or capillaries. The smooth muscle cells contraction is mainly regulated by the intracellular calcium concentration.

Renin-Angiotensin-Aldosterone System:

This is one of the very important endocrine systems associated directly with regulation of BP. Renin plays a critical role in the pathogenesis of hypertension6, is secreted from kidney in response to reduced salt intake as well as the stimulation from sympathetic nervous system. Renin converts angiotensinogen to angiotensin I, a physiologically in active substance which is rapidly converted to angiotensin II in the lungs by angiotensin converting enzyme. Angiotensin II is a potent vasoconstrictor and thus causes an increase in BP. Also, it stimulates the release of aldosterone, which results in reabsorption of sodium and water, leading to plasma volume expansion and also it acts through nongenomic mineralocorticoid receptor mediated responses7and hence increases in BP.

The circulating renin-angiotensin system may not be directly responsible for the increase in BP in primary hypertension as many hypertensive patients have been found to have low levels of renin and angiotensin II, and drugs that block the renin-angiotensin system are not particularly effective. The non-circulating “local” renin-angiotensin epicrine or paracrine systems have also been reported, which may have important roles in regulating regional blood flow as well as maintaining BP8.

Autonomic Nervous System:

Sympathetic nervous system has an important role in maintaining normal BP as its stimulation can cause both arteriolar constriction as well as dilatation. Patients with essential hypertension show the evidence of increased activity of muscle sympathetic nerve9and augmented cardiac and renal noradrenaline release from the sympathetic nerves10,11. Hyperactivity of sympathetic system has also been shown closely associated to hypertension-related end organ damage12, 13, 14. Interaction between the autonomic nervous system and the renin-angiotensin system along with other factors including sodium level and blood volume has also been suggested having significant association with hypertension15.

Endothelial Dysfunction:

Dysfunction of the endothelium has been correlated with hypertension. The endothelium senses biochemical signals from circulation and, in turn, releases vasodilator such as nitric oxide (NO) and the vasoconstrictor peptide, endothelin (ET)16. The role of NO has been described in patients with essential hypertension showing a determinant for the premature development of atherosclerosis17. Further, several studies have reported the influence of NO on stimulating soluble guanylyl cyclase activity in vascular smooth muscle cells18impairing BP and cellular events such as renal hemodynamics, vasodilation, leukocyte adhesion and cellular proliferation and thrombosis19, 20. Besides, ET-1 is also considered to be an important factor in the development of vascular dysfunction and cardiovascular complications beyond pulmonary arterial hypertension21.

Obesity and Insulin Resistance:

Insulin resistance is another important risk factors in the development of hypertension in both normal and obese individuals22, 23, 24. Hypertension in diabetes patients is common and is characterized by increased peripheral vascular resistance and elevated BP25, 26. It is shown that the hypertension coexists with renal disease in type I diabetic patients. Further, in type II diabetics, the hyperinsulinemic insulin-resistant syndrome is frequently accompanied by hypertension, even in the absence of obesity22, 23, 27. It is also shown that hypertensive patients exhibited increased circulating insulin levels compared with normotensives of comparable glucose tolerance even after compromising the differences in body weight27. Other hand, the obese individuals have been observed having the elevated sodium retention and volume expansion along with increased sympathetic nervous activity and stimulation of the rennin-angiotensin system28. Thus studies describe that several risk factors including obesity, glucose intolerance, diabetes mellitus, and hyperlipidaemia cluster together, leading to the complex pathophysiology of hypertension in patients.

Molecular Mechanism of Hypertension

During hypertension, expression of many molecules including phospholipase C-inositol phosphate-diacylglycerol, mitogen-activated protein kinase, tyrosine kinases/phosphatases, RhoA/Rhokinase, transcription factors and NADPH and oxidase-derived reactive oxygen species (ROS) are changed in response to altered cellular functions29, 30, 31. Various prehypertensive peptides such as angiotensin-II and endothelin-1, which signal through membrane associated G protein-coupled receptors, are also associated with stimulation of the above signaling pathways32, 33. In addition, aldosterone, through their intracellular mineralocorticoid receptor, has also been shown to influence cardiac and vascular function in hypertensive patients34. The importance of aldosterone in the pathogenesis of hypertension has recently been supported by the findings of a mutation of the Kþ channel35.

In hypertension, the bioavailability of vasodilator NO is reduced significantly, other hand vasoconstrictor ET-1 activity is increased36. Due to activation of guanylate cyclase by NO, there is an increase in cyclic GMP levels in smooth muscle cells, which leads to vasodilatation. It is reported that overproduction of endothelial nitric oxide synthase (eNOS), which synthesizes NO, in transgenic mice prevented pulmonary hypertension (PH) induced by hypoxia37. In eNOS-deficient mice, exposure to mild hypoxia even resulted a severe form of PH38, 39. The mechanism of action of NO-induced vasodilation is based on activation of Ca2+-dependent K+ channels and increase the outward potassium flow40. Cell membrane thus gets hyperpolarized and decreases the effect of the depolarizing signals and induces vasodilation.

Studies in human utilizing selective and nonselective ET-1 receptor antagonists demonstrated the crucial role of ET-1 in vasoconstriction36, 41. In hypertension modulating cardiovascular pathway, ET-1 activity has been linked commonly to aldosterone. Aldosterone has multiple actions through rapid nongenomic and genomic pathways involving mineralororticoid-dependent as well as -independent signaling, in the heart, the vessels and other non epithelial tissues42. Besides, the angiotensin II signaling through receptor tyrosine kinases involves Ang II type1 receptor (AT1) mediated transactivation of these kinases in vascular remodeling43. Other hand, AT2 receptor stimulation has been reported promoting cardiovascular protection through anti-fibrotic and anti-inflammatory actions without having anti-hypertensive effects.

Other important mechanism also has been described in developing hypertension by activating factors such as G protein RhoA and its target protein Rho kinase via the inhibition of myosin light chain phosphatase activity44, 45, 46. RhoA is phosphorylated at Ser188 by PKG-I, which inhibits its membrane association and thus prevents activation of its downstream targets, such as Rho kinase47, 48. Thus, RhoA and Rho kinase contribute to sustained vasoconstriction and vascular functions by regulating various cell functions49, 50. RhoA-Rhokinase signaling pathway has been shown to be involved in various pulmonary vascular disorders under hypoxic conditions51, 52, 53. An increased RhoA and Rho kinase activity with concomitant increased Rho kinase expression was observed in pulmonary vascular smooth muscle exposed to chronic hypoxic conditions54. Rho kinase has been linked to endothelial nitric oxide synthase (eNOS) activity, as an increase in eNOS protein was observed in Rho kinase inhibitor-treated lungs during hypoxia exposure, suggesting that an upregulation of eNOS is involved in inhibiting the pulmonary vasoconstriction55. Moreover, pulmonary arteries have been shown to have increased sensitivity to NO on exposure to chronic hypoxia56, 57.

Reactive oxygen species has been related to NO signaling, showing that the increase in both ROS and Rho kinase activities reduce synthesis of endothelium-derived NO58, 59, thereby increasing vasoconstriction leads to hypertension. NADPH oxidase (Nox) has been shown to be the major source for the generation of ROS in vascular smooth muscle cells60, endothelial cells61, and fibroblasts62. Increased expression of Nox4 (an isoform of Nox) in the vasculature of hypertensive patients may disrupt the NO signaling through a number of pathways63. In hypoxia-induced murine model of PH, an increase in Nox4 expression was reported in vascular smooth muscle cells, which clearly indicated a crucial role of Nox in PH pathophysiology64. Thus the studies suggest that all these molecules are interconnected to each other via different pathways and upon interaction lead to PH.

Hypoxia and Hypertension

Hypoxia has critical impact on the pulmonary hypertension (PH). Pulmonary artery pressure gets elevated chronically in people living at high altitude, which supports the idea that hypoxia alone can cause PH65. A number of primary lung diseases are also known to be associated with chronic hypoxia, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, diffuse interstitial fibrosis, bronchopulmonary dysplasia, radiation fibrosis, infiltrative lung tumors, and collagen vascular disease66, 67, 68, 69, 70, 71, 72. Neuromuscular and skeletal disorders such as scoliosis, Duchenne muscular dystrophy, and poliomyelitis may also impair ventilation and be associated with hypoxia-induced PH66, 73. Hypoxic condition has long been recognized to play a significant role in the pathogenesis and progression of chronic renal disease. During hypoxia the hypoxia inducible factor (HIF) is elevated regulating several important cellular processes such as angiogenesis, vasotone, glucose metabolism and cell survival. In renal disorder, HIF activation is well described showing its role in disease progression. The hypoxia exposure also has been shown to promote significantly the renal injury by increasing hypertension74.

High Altitude Hypoxia and Hypertension

Native sea level dwellers when migrate to high altitude, develop increased pulmonary vascular resistance and hypertension due to adverse hypoxic exposure75. Further, they also develop hypoxia associated respiratory diseases including chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep disordered breathing and some rare neonatal disease76.

In normal condition, the mean pulmonary arterial pressure (mPAP) of an individual exists under 25 mm Hg (generally, 12 at resting condition and 16 mm Hg at exercise)77 while in case of pulmonary hypertension (PH) it is increased above 25 mm Hg at rest and 30 mm Hg at exercise accordingly. The degree of PH ordinarily is modest at tolerable altitudes but may approach systemic levels when alveolar hypoventilation and systemic arterial hypoxemia are severe, as in chronic mountain sickness78, 79.

Pathophysiology of Hypoxia Induced Hypertension

Chronic hypoxia induces structural changes in pulmonary arteries, and in the biochemical and functional phenotypes of the vascular cells80. When alveolar hypoxia is prolonged, pulmonary vasoconstriction occurs and is compensated by a rise in pulmonary arterial pressure, which is further accompanied by structural changes in small peripheral pulmonary arteries, including increased thickness of arterial walls81, 82. Commonly such changes are occurred in patients with chronic obstructive airways disorder83.

Another characteristic feature of hypoxic pulmonary hypertension is luminal vascular obstruction caused by smooth muscle cells proliferation, thrombosis and vasoconstriction. These changes reflect a homeostatic imbalance characterized by disproportion between secreted vasodilators and constrictors that affect growth and thrombosis. Furthermore, persistent structural alterations of the small pulmonary arterioles are believed to be associated with the complex pathophysiology of pulmonary vascular lesions (plexiform lesions) in patients suffering from severe PH84, 85.

Molecular Mechanism of Hypoxia Regulation of Hypertension

In hypoxic hypertension, the thickening of pulmonary arteries (PA) is common86, 87, 88. The thickening of the arterial walls is believed to be caused by hypertrophy and increased accumulation of smooth muscle cells as along with increased deposition of extracellular matrix proteins such as collagen, elastin, fibronectin and tenascin89, 90, 91.

A number of the above such acclimatization mechanisms are regulated by hypoxia responsive genes, which ensure cellular and systemic functions under hypertensive conditions. Expression and activation of oxygen responsive transcription factors are regulated by alterations in partial pressure of oxygen (pO2) that may either be due to reduction in oxygen delivery or malfunctioning in oxygen utilization at cellular level. HIF-1 is believed to be the main transcription factor mediating these molecular responses, besides other transcription factors such as, early growth response-1 (Egr-1), nuclear factor kappa B (NF-kB) and nuclear factor of activated T cells (NFAT) are also involved.

HIF-1 is a heterodimer composed of an oxygen-regulated HIF-1α subunit and constitutively expressed HIF-1β subunit of the Per-Arnt-Sim (PAS) family proteins92, 93. These proteins bind to consensus DNA binding motifs within regulatory promoter regions, hypoxia-responsive elements (HREs) of hypoxia-responsive genes. HIF-1α is rapidly degraded by the ubiquitin-proteasome system by specific prolyl hydroxylase-domain (PHDs) enzymes, which initiates its degradation via von Hippel-Lindau tumor suppressor protein (VHL) by a process that requires the presence of two sequences in HIF-1α termed oxygen dependent degradation domains94, 95, 96, 97. The hydroxylation of proline residues 402 and 564 of the α-subunit of HIF-1 facilitate interaction with the VHL tumor suppressor that targets HIFα for proteasomal degradation. In hypoxia, oxygen dependent proline and asparagine hydroxylation are inhibited and HIF-α accumulates. It binds to the constitutively expressed nuclear protein HIF-1β, translocates to the nucleus, associates with co-activators, docks with HREs in target genes and becomes transactivated to regulate transcription. HIF-1α is the most ubiquitously expressed and is recognized as a master regulator of hypoxic signaling98.

In hypoxic hypertension, the HIF-1α promotes the upregulation of ET-1. It has been demonstrated that the ET-1 transcription is significantly increased by hypoxia via recruitment of several nuclear factors including HIF-1, AP-1, GATA-2, CAAT-binding factor (NF-1) and CREB binding protein (p300/CBP)99, 100, 101. In an animal model with obstructive sleep apnea, a crucial role of HIF-1 and ET-1 in promoting hypertension has been described102. Another in vivo study using spontaneous hypertensive rats (SHR) shows an elevated hypertensive condition in response to hypoxic exposure with an increase in myocardial pre-pro ET-1 levels and ET-A receptor expression. HIF-1α targeting ET-1 gene in SHR was also evident from the finding that myocardial HIF-1 activity was increased during hypertension. The role of ET in hypertension was also demonstrated by administration of bosentan, an ET receptor antagonist, to mice, which prevented both increase in BP and infarct size. Thus study demonstrated that activation of ET system, mediated by HIF-1 activity, is responsible for the enhanced susceptibility cardiovascular problems, leading to hypertension and ischemic injury103. HIF has also been known to regulate expression of RhoA with concomitant downregulation of Rho kinase, in PH104.

The early growth response-1 (Egr-1) is a zinc finger-binding domain containing transcription factor also play important role in maintaining cellular functions in response to hypoxia. Egr-1 has strong binding affinity to a consensus DNA element to modulate the expression of genes involved in synaptic plasticity, cell growth and survival, extracellular matrix remodeling and thrombosis105. Nuclear localization of Egr-1 is enhanced under hypoxic conditions, which is necessary for synthesis of procoagulant tissue factor. It has been reported that Egr-1 activation under hypoxic condition is independent of HIF106. Also, other molecules including the members of the protein kinase C (PKC) family have been identified as the crucial initiators to Egr-1. PKCb null mice revealed markedly decreased Egr-1 levels in response to hypoxia107. Furthermore, PKCa as well as the active downstream molecules such as Ras/Raf/ERK1/2 are implicated in Egr-1 gene induction in endothelial cells during hypoxia108. Thus studies show that the hypoxia induced Egr-1 expression is an important regulatory event that contributes to the pathogenesis of pulmonary thrombosis and vascular remodeling109, 110.

The NF-κB is an important mediator of inflammatory responses and is associated with induction of hypertension and vascular damage. NF-κB is a member of the Rel family of proteins and was first described as a nuclear factor in B cells111. NF-κB upregulates the transcription of several proinflammatory genes including tumor necrosis factor (TNF-α), interleukin (IL-6 and IL-8), chemokines and surface adhesion molecule (intercellular adhesion molecule-1, ICAM-1)112. Activity of NF-κB and TNF-α level are also known to be increased in cells and animals exposed to hypoxia treatment and also in hypertensive patients. TNF-α has been shown to play a major role in inflammation mediated vascular damage in hypertensive patients and animal models113.

The nuclear factor of activated T cells (NFAT) has been shown to be associated in the development of hypoxic hypertension114and cardiovascular function115. The NFAT transcription factor mediates binding of the Ca2+-activated phosphatase calcineurin and other regulatory functions necessary for nuclear translocation. It also contains nuclear localization and export sequences along with phosphorylation sites for a number of serine/threonine kinases. When intracellular Ca2+ level increases, an increased calcineurin activity is observed115, 116. It was reported that systemic hypertension caused by hypoxia in mice is associated with NFATc3 activation in aorta and mesenteric arteries114. It was also reported that genetic ablation or pharmacological inhibition of NFATc3 prevents hypoxia induced hypertension, showing the importance of NFAT in hypoxia induced cardiovascular pathology117, 118.

Hypertension and Hypercoagulation at High Altitude

The evidence of hypercoagulability states and pulmonary hypertension (PH) is common in travelers at high altitude under adverse hypoxic conditions119. For lowlanders, traveling in a short time at high altitudes (2500 to 5000 meters above sea level), can lead to acute health problems. Further, patients with PH when travel to high altitude, get pulmonary vasoconstriction which further causes increase in pulmonary artery pressure, which may worsen hemodynamics and also predispose to acute altitude illness120. During travel, basal metabolic rate (BMR) increases by approximately 17-27% for the first few weeks upon exposure to high altitude and gradually returns toward sealevel baseline121. Also, the highest oxygen uptake an individual can attain is decreased by approximately 20-30% during the first weeks and gradually returns toward normal over the course of 1 year122, 123.

Hypercoagulation state is resulted due to complex interplay between the coagulation and fibrinolytic pathways. Hypoxia activates the transcription factor, Egr-1, leading to de novo transcription/translation of tissue factor, which results in vascular fibrin deposition. The procoagulant response is magnified by concomitant suppression of fibrinolysis by hypoxia-mediated upregulation of plasminogen activator inhibitor-1 (Pai-1). Interaction between fibrinolysis promoting and inhibiting factors like tissue plasminogen activator (tPA) and Pai-1 respectively, affect the fibrinolytic system. Thus, the hypertensive state leading to hypercoagulability may be evident from the travelers to the high altitude with elevated BP and thrombosis related complications including strokes and cardiac attacks.

Other hand, the people living at high altitudes for generations develops physiological adaptations to counter the extreme hypoxic conditions. A huge difference in pulmonary artery pressure was reported between individuals in response to hypoxia. Studies in the town of Leadville (3100 meters above sea level) in the Colorado Rockies showed that the degree of PH measured at right heart catheterisation varied from individual to individual, with some individuals demonstrating marked elevation of pulmonary arterial pressure124. These observations are consistent with differing genetic susceptibilities to hypoxia induced PH. Genetic factors have also been shown to be involved in the control of the pulmonary vascular response to hypoxia125. In Tibetan population, a greater increase in blood flow in brain was observed during exercise126as compared with lowlanders. The Tibetans exhibit less PH than the inhabitants of the Peruvian Andes, who in turn are less susceptible than recent immigrants to high altitude, such as Caucasian Americans, and the Han Chinese in Tibet. Tibetans who were born and raised at high altitude were found to have higher capillary density in muscles as compared with Andean high altitude natives, Tibetans born and raised at low altitude, or low landers127, which could potentially improve perfusion and oxygen delivery, because each capillary would supply a smaller area of tissue, and oxygen would diffuse a shorter distance. It seems from these studies of people living at high altitude that it is genetically advantageous to exhibit a blunted cardiovascular response to chronic hypoxia, and that the susceptibility to hypoxia induced PH is bred out over many generations. Thus genes, which provide susceptibility to hypoxia induced PH could exist in high altitude populations. In Tibetan population living at high altitude, adaptation has been linked to EPAS1/HIF2A gene128. Between Han Chinese, Japanese population and Tibetan high altitude dwellers, EPAS1/HIF2A exhibited a significant signal for a cross population test for natural selection (XP-EHH)129, 130. In Tibetan population, it has also been shown that variation in EPAS1/HIF2A is associated with lower Hb concentration131, 132. Study also report common polymorphism in the gene for angiotensin converting enzyme and susceptibility to high altitude PH in highlanders from the Kyrgyz Republic in Central Asia133.

Diagnosis

Pulmonary hypertension (PH) is often present with nonspecific symptoms like dyspnea on exertion, fatigue, syncope, anginal chest pain, hemoptysis (rupture of distended pulmonary vessels) and Raynaud's phenomenon, which are very difficult to be dissociated from those caused by a known underlying pulmonary or cardiac disorder. Cardiac output is decreased during exertional dyspnea, fatigue and syncope Reynaud’s phenomenon occurs in approximately 2 percent of patients with primary pulmonary hypertension but is more common in patients with pulmonary hypertension related to connective tissue disease134. For diagnosis of PH, a high index of suspicion, a meticulous history and a careful physical and medical examination including use of drugs and family history are necessary for the diagnosis of PH. PH patients have of right ventricular hypertrophy in electrocardiogram (ECG) or prominent pulmonary arteries on the chest radiograph.

Besides, 2D echocardiography with Doppler flow studies is also performed in patients with PH. Among other tests complete blood count, prothrombin time, partial thromboplastin time, hepatic profile and autoimmune panel are also followed in PH patients135. Hypoxia induced PH could also be checked by arterial blood gas analysis, as pulmonary function is highly reduced in this state.

Treatment

Although many excellent antihypertensive agents are commercially available, millions of hypertensive patients do not have their BP under control and ultimately face the extreme problems of cardiovascular disease. Most of the hypertensive drugs for controlling PH are aimed at relatively few targets136. But still there exists lot many issues regarding treatment of hypertension including expensive drugs and therefore less availability and detection of hypertension itself is a big problem. Thus there is clear need of proper treatment for hypertensive patients and for this to be achieved several important therapeutic principles are to be considered. The use of diuretics including thiazides is considered as first line of therapy for hypertension. In addition, a beta-adrenoreceptor (β- blocker) is used for treating PH. If the response is still inadequate then calcium channel blocker is generally suggested to the patients. Finally, if this combination does not work or is not tolerated, an ACE inhibitor is then substituted. The pharmacological agents could be effective, potential drawbacks include the need for continuous i.v. infusion of vasodilators with potential side effects. The above drugs commonly target the pathways including renin-angiotensin system, adrenergic or adrenergic receptors, and calcium channels.

References

  1. 1.Huang L E, Gu J, Schau M, Bunn H F. (1998) Regulation of hypoxia-inducible factor 1a is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proceedings of the National Academy of Sciences USA 95, 7987-92.
  1. 2.Pugh C W, O’Rourke J F, Nagao M, Gleadle J M, Ratcliffe P J. (1997) Activation of hypoxia-inducible factor-1 definition of regulatory domains within the a subunit. , J Biol Chem 272, 11205-14.
  1. 3.Salceda S, Caro J. (1997) Hypoxia-inducible factor 1a (HIF-1a) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. , J Biol Chem 272, 22642-7.
  1. 4.Semenza G L. (2004) Hydroxylation of HIF-1: oxygen sensing at the molecular level. , Physiol 19, 176-182.
  1. 5.Hu J, Discher D J, Bishopric N H, Webster K A. (1998) Hypoxia regulates expression of the endothelin-1 gene through a proximal hypoxia-inducible factor-1 binding site on the antisense strand. , Biochem Biophys Res Commun 245, 894-9.
  1. 6.Minchenko A, Caro J. (2000) Regulation of endothelin-1 gene expression in human microvascular endothelial cells by hypoxia and cobalt: role of hypoxia responsive element. , Mol Cell Biochem 208, 53-62.
  1. 7.Yamashita K, Discher D J, Hu J, Bishopric N H, Webster K A. (2001) Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1 GATA-2, and p300/CBP. , J Biol Chem 276, 12645-53.
  1. 8.Belaidi E, Joyeux-Faure M, Ribuot C, Launois S H, Levy P. (2009) Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea. , J American College Cardiology 53, 1309-17.
  1. 9.LVG Bosc, Resta T, Walker B, Kanagy N L. (2010) Mechanisms of intermittent hypoxia induced hypertension. , J Cell Mol Med 14, 3-17.
  1. 10.Greijer A E, vanderGroep P, Kemming D, Shvarts A, Semenza G L. (2005) Up-regulation of gene expression by hypoxia is mediated predominantly by hypoxia-inducible factor 1 (HIF-1). , J Pathol 206, 291-304.
  1. 11.Thiel G, Cibelli G. (2002) Regulation of life and death by the zinc ?nger transcription factor Egr-1. , J Cell Physiol 193, 287-92.
  1. 12.Yan S F, Zou Y S, Gao Y, Zhai C, Mackman N. (1998) Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary ?brin deposition in hypoxia. Proc Natl Acad Sci USA 95, 8298-303.
  1. 13.Yan S F, Lu J, Zou Y S, Kisiel W, Mackman N. (2000) Protein kinase C-b and oxygen deprivation A novel Egr-1-dependent pathway for ?brin deposition in hypoxemic vasculature. , J Biol Chem 275, 11921-8.
  1. 14.Lo L W, Cheng J J, Chiu J J, Wung B S, Liu Y C. (2001) Endothelial exposure to hypoxia induces Egr-1 expression involving PKC alpha-mediated Ras/Raf-1/ERK1/2 pathway. , J Cell Physiol 188, 304-12.
  1. 15.Semenza G L. (2000) Oxygen-regulated transcription factors and their role in pulmonary disease. , Respir Res 1, 159-62.
  1. 16.Yan S F, Mackman N, Kisiel W, Stern D M, Pinsky D J. (1999) Hypoxia/hypoxemia-Induced activation of the procoagulant pathways and the pathogenesis of ischemia-associated thrombosis. , Arterioscler Thromb Vasc Biol 19, 2029-35.
  1. 17.Sen R, Baltimore D. (1986) Inducibility of [kappa] immunoglobulin enhancer-binding protein NF-[kappa]B by a posttranslational mechanism. , Cell 47, 921-8.
  1. 18.Fraser C C. (2008) G Protein-Coupled Receptor Connectivity to NF-kB in Inflammation and Cancer. , Int Rev Immunol 27, 320-50.
  1. 19.Garvey J F, Taylor C T, McNicholas W T. (2009) Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. , Eur Respir J 33, 1195-205.
  1. 20.deFrutos S, Duling L, Alò D, Berry T, Jackson-Weaver O. (2008) NFATc3 is required for intermittent hypoxia-induced hypertension. , Am J Physiol Heart Circ Physiol 294, 2382-90.
  1. 21.Hill-Eubanks D C, Gomez M F, Stevenson A S, Nelson M T. (2003) . , NFAT Regulation in Smooth Muscle. Trends Cardiovasc Med 13, 56-62.
  1. 22.Rao A, Luo C, Hogan P G. (1997) Transcription factors of the NFAT family: regulation and function. , Annu Rev Immunol 15, 707-47.
  1. 23.Gonzalez Bosc LV, Layne J J, Nelson M T. (2004) Hill-Eubanks DC. Nuclear factor of activated T-cells and serum response factor cooperatively regulate an ?-actin intronic enhancer. , J BiolChem 280, 26113-20.
  1. 24.deFrutos S, Spangler R, Alò D, Bosc L V. (2007) NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. , J Biol Chem 282, 15081-9.
  1. 25.Johnson S R, Granton J T, Mehta S. (2006) Thrombotic arteriopathy and anticoagulation in pulmonary hypertension. , Chest 130, 545-52.
  1. 26.Luks A M. (2009) Can patients with pulmonary hypertension travel to high altitude?. , High Alt Med Biol Fall 10(3), 215-9.
  1. 27.Butter field GE, Gates J, Fleming S, Brooks G A, Sutton J R. (1992) Increased energy intake minimizes weight loss in men at high altitude. , J App Physiol 72, 1741-8.
  1. 28.Ward M P, Milledge J S, West J B, Ed3BrJSportsMed. (2001) . In High Altitude Medicine Physiology. OxfordUnivPress , London 35, 434-451.
  1. 29.Buskirk E R, Little M A, Dowden. (1976) In Man in the Andes: A Multidisciplinary Study of High Altitude Quechua,. Ed Baker PT,Little MA,Dowden. , Hutchinson, and Ross, Stroudsburg, PA 283-99.
  1. 30.HJK Vogel, Weaver W F, Rose L D.150 feet (Leadville. (1963)Pulmonary hypertension on exertion in normal man living at 10 Colorado). In Normal and abnormal pulmonary circulation. Ed Grover RF, Basel:S,Karger. 289-91.
  1. 31.Reeves J T, Durmowicz A G. (1996) High altitude and the pulmonary circulation. In Pulmonary circulation: a handbook for physicians. Ed Peacock AJ London: Chapman and Hall. 262-72.
  1. 32.Huang S Y, Sun S, Droma T, Zhuang J, Tao J X. (1992) Internal carotid arterial flow velocity during exercise in Tibetan and Han residents of Lhasa (3,658 m). , J Appl Physiol 73, 2638-42.
  1. 33.Hoppeler H, Vogt M, Weibel E, Fluck M. (2003) Response of Skeletal Muscle Mitochondria to Hypoxia. Exp Physiol. 88, 109-19.
  1. 34.Simonson T S, Yang Y, Huff C D, Yun H, Qin G. (2010) Genetic evidence for high-altitude adaptation in Tibet. , Science 329(5987), 72-5.
  1. 35.Sabeti P C, Varilly P, Fry B, Lohmueller J, Hostetter E. (2007) Genome-wide detection and characterization of positive selection in human populations. , Nature 449(7164), 913-8.
  1. 36.Consortium HapMap. (2007) A second generation human haplotype map of over 3.1 million SNPs. , Nature 449(7164), 851-61.
  1. 37.Beall C M, Cavalleri G L, Deng L, Elston R C, Gao Y. (2010) Natural selection on EPAS1 (HIF2a) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci 107(25), 11459-64.
  1. 38.Yi X, Liang Y, Huerta-Sanchez E, Jin X, ZXP Cuo. (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. , Science 329(5987), 75-8.
  1. 39.Morrell N W, Sarybaev A S, Alikhan A, Mirrakhimov M M, Aldashev A. (1999) ACE genotype and risk of high altitude pulmonary hypertension in Kyrghyz highlanders. , Lancet 353, 814.
  1. 40.Gurubhagavatula I, Palevsky H I. (1997) Pulmonary hypertension in systemic autoimmune disease. , Rheum Dis Clin North Am 23, 365-94.
  1. 41.Nauser T D, Stites S W. (2001) Diagnosis and Treatment of Pulmonary Hypertension. , Am Fam Physician 63(9), 1789-99.
  1. 42.Phillips M I. (2001) Gene Therapy for Hypertension: The Preclinical Data. , Hypertension 38, 543-8.
  1. 43.Pierdomenico S D, M Di Nicola, Esposito A L, R Di Mascio, Ballone E. (2009) Prognostic value of different indices of blood pressure variability in hypertensive patients. , Am J Hypertens 22(8), 842-7.
  1. 44.Carretero O A, Oparil S. (2000) Essential hypertension Part I: definition and etiology. , Circulation 101(3), 329-35.
  1. 45.Tabassum N, Ahmad F. (2011) Role of natural herbs in the treatment of hypertension. , Pharmacog Rev 5(9), 30-40.
  1. 46.Chiong J R, Aronow W S, Khan I A, Nair C K, Vijayaraghavan K. (2008) Secondary hypertension: current diagnosis and treatment. , Int J Cardiol 124(1), 6-21.
  1. 47. (2012) World Health Statistics Report. New data highlight increases in hypertension diabetes incidence.http://www.who.int/mediacentre/news/releases/2012/world_health_statistics_20120516/en.
  1. 48.Laragh J H. (1992) The renin system and four lines of hypertension research. , Hypertension 20, 267-79.
  1. 49.Cooper S A, Whaley-Connell A, Habibi J, Sowers J R. (2007) Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance. , Am J Physiol Heart Circ Physiol 293, 569-82.
  1. 50.Beevers G, GYH Lip, O’B Eoin. (2001) ABC of hypertension The pathophysiology of hypertension. , BMJ 322, 912-6.
  1. 51.Anderson E A, Sinkey C A, Lawton W J, Mark A L. (1989) Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings. , Hypertension 14, 177-83.
  1. 52.Esler M, Lambert G, Jennings G. (1989) Regional norepinephrine turnover in human hypertension. Clin Exp Hypertens A.11(suppl1): 75-89.
  1. 53.Schlaich M P, Lambert E, Kaye D M, Krozowski Z, Campbell D J. (2004) Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and angiotensin neuromodulation. , Hypertension 43, 169-75.
  1. 54.Mancia G, Grassi G, Giannattasio C, Seravalle G. (1999) Sympathetic activation in the pathogenesis of hypertension and progression of organ damage. , Hypertension 34, 724-8.
  1. 55.Schlaich M P, Kaye D M, Lambert E, Sommerville M, Socratous F. (2003) Relation between cardiac sympathetic activity and hypertensive left ventricular hypertrophy. , Circulation 108, 560-5.
  1. 56.Grassi G, Seravalle G, Quarti-Trevano F, Dell'Oro R, Arenare F. (2009) Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. , Hypertension 53, 205-9.
  1. 57.Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto F A. (2002) Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. , Circulation 105, 1354-9.
  1. 58.Corti R, Fuster V, Badimon J J. (2003) Pathogenetic concepts of acute coronary syndromes. , J Am Coll Cardiol 41, 7-14.
  1. 59.Lowenstein C J, Dinerman J L, Snyder S H. (1994) Nitric oxide a physiologic messenger. , Ann Intern Med 120, 227-37.
  1. 60.Joannides R, Haefeli W E, Linder L, Richard V, Bakkali E H. (1995) Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. , Circulation 91, 1314-9.
  1. 61.Cowley A W, Roman R J. (1996) The role of the kidney in hypertension. , JAMA 275, 1581-9.
  1. 62.Fuster V, Moreno P R, Fayad Z A, Corti R, Badimon J J. (2005) Atherothrombosis and high-risk plaque: part I-evolving concepts. , J Am Coll Cardiol 46, 937-54.
  1. 63.Böhm F, Pernow J. (2007) The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. , Cardiovas Res 76, 8-18.
  1. 64.Ferrannini E, Buzzigoli G, Bonadonna R, Giorico M A, Oleggini M. (1987) Insulin resistance in essential hypertension. , N Engl J Med 317, 350-7.
  1. 65.Modan M, Halkin H, Almay S, Lusky A, Eshkil M. (1985) Hyperinsulinemia: a link between hypertension, obesity and glucose intolerance. , J Clin Invest 75, 809-17.
  1. 66.Sowers J R, Khoury S, Standley P, Zemel P, Zemel M. (1991) Mechanisms of hypertension in diabetes. , Am J Hypertension 4, 177-82.
  1. 67.Christlieb A R. (1976) Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects. , Diabetes 25, 268-74.
  1. 68.Sowers J R, Zemel M B. (1990) Clinical implications of hypertension in the diabetic patient. , Am J Hypertension 3, 415-24.
  1. 69.Christlieb A R, Krolewski A S, Warram J H, Soeldner J S. (1985) Is insulin the link between hypertension and obesity?. Hypertension. 7(suppl II): 54-7.
  1. 70.Engeli S, Sharma A M. (2000) Role of adipose tissue for cardiovascular-renal regulation in health and disease. Horm Metab Res. 32, 485-489.
  1. 71.Kahle K T, Rinehart J, Giebisch G, Gamba G, Hebert S C. (2008) A novel protein kinase signaling pathway essential for blood pressure regulation in humans. , Trends Endocrinol Metab 19, 91-5.
  1. 72.Briones A M, Touyz R M. (2010) Oxidative stress and hypertension: current concepts. Curr Hypertens Rep. 12, 135-42.
  1. 73.Fisher S A. (2010) Vascular smooth muscle phenotypic diversity and function. Physiol Genomics. 42, 169-187.
  1. 74.Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank G D. (2007) Angiotensin-II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. , Clin Sci (Lond) 112, 417-28.
  1. 75.Bastin G, Heximer S P. (2011) Intracellular regulation of heterotrimeric G-protein signaling modulates vascular smooth muscle cell contraction. , Arch Biochem Biophys 510, 182-89.
  1. 76.Rautureau Y, Paradis P, Schiffrin E L. (2011) Cross-talk between aldosterone and angiotensin signaling in vascular smooth muscle cells. , Steroids 76, 834-9.
  1. 77.Choi M, Scholl U I, Yue P, Björklund P, Zhao B. (2011) KR channel mutations in adrenal aldosterone producing adenomas and hereditary hypertension. , Science 331, 768-72.
  1. 78.Stauffer B L, Westby C M, DeSouza C A. (2008) Endothelin-1, aging and hypertension. , Curr Opin Cardiol 23, 350-5.
  1. 79.Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y. (2001) Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. , Hypertension 37, 322-7.
  1. 80.Fagan K A, Fouty B W, Tyler R C, Morris KG Jr, Hepler L K. (1999) The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. , J Clin Invest 103, 291-9.
  1. 81.Steudel W, Ichinose F, Huang P L, Hurford W E, Jones R C. (1997) Pulmonary vasoconstriction and hypertension in mice with targeted disruption of the endothelial nitric oxide synthase (NOS 3) gene. Circ Res. 81, 34-41.
  1. 82.Bolotina V M, Najibi S, Palacino J J, Pagano P J, Cohen R A. (1994) Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. , Nature 368, 850-3.
  1. 83.Van Guilder GP, Westby C M, Greiner J J. (2007) Endothelin-1 vasoconstrictor tone increases with age in healthy men but can be reduced by regular aerobic exercise. , Hypertension 50, 403-409.
  1. 84.AND Cat, Jaisser F. (2012) Extra-renal effects of Aldosterone. , Curr Opin Nephrol Hypertens 21(2), 147-56.
  1. 85.Batchu S N, Korshunov V A. (2012) Novel tyrosine kinase signaling pathways: implications in vascular remodeling. Curr Opin Nephrol Hypertens. 21(2), 122-7.
  1. 86.Feil R, Lohmann S M, H de Jonge, Walter U, Hofmann F. (2003) Cyclic GMP-dependent protein kinases and the cardiovascular system: insights from genetically modified mice. Circ Res. 93, 907-16.
  1. 87.Stephens R S, Rentsendorj O, Servinsky L E, Moldobaeva A, Damico R. (2010) cGMP increases antioxidant function and attenuates oxidant cell death in mouse lung microvascular endothelial cells by a protein kinase G-dependent mechanism. , Am J Physiol Lung Cell Mol Physiol 299-323.
  1. 88.Feng J, Ito M, Ichikawa K, Isaka N, Nishikawa M. (1999) Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. , J Biol Chem 274, 37385-90.
  1. 89.Sawada N, Itoh H, Yamashita J, Doi K, Inoue M. (2001) cGMP-dependent protein kinase phosphorylates and inactivates RhoA. , Biochem Biophys Res Commun 280, 798-805.
  1. 90.Sauzeau V, H Le Jeune, Cario-Toumaniantz C, Smolenski A, Lohmann S M. (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. , J Biol Chem 275, 21722-9.
  1. 91.Hu E, Lee D. (2003) Rho kinase inhibitors as potential therapeutic agents for cardiovascular diseases. , Curr Opin Investig Drugs 4, 1065-75.
  1. 92.Shimokawa H, Takeshita A. (2005) Rho-kinase is an important therapeutic target in cardiovascular medicine. , Arterioscler Thromb Vasc Biol 25, 1767-75.
  1. 93.Fagan K A, Oka M, Bauer N R, Gebb S A, Ivy D D. (2004) Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. , Am J Physiol Lung Cell Mol Physiol 287, 656-64.
  1. 94.Guilluy C, Sauzeau V, Rolli-Derkinderen M, Guerin P, Sagan C. (2005) Inhibition of RhoA/Rho kinase pathway is involved in the bene?cial effect of sildena?l on pulmonary hypertension. , Br J Pharmacol 146, 1010-18.
  1. 95.Hyvelin J M, Howell K, Nichol A, Costello C M, Preston R J. (2005) Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation. Circ Res. 97, 185-91.
  1. 96.Jemigan N L, Walker B R, Resta T C. (2004) Chronic hypoxia augments protein kinase G-mediated Ca2+ desensitization m pulmonary vascular smooth muscle through inhibition of RhoA/Rho kinase signaling. , Am J Physiol Lung Cell Mol Physiol 287(6), 220-29.
  1. 97.Pagan K A, Oka M, Sauer N R, Gebb S A, ivy D D. (2004) Attenuation of aatla hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinase. , Arn J Physiol Lung Ceil Mol Physiol 287(4), 656-64.
  1. 98.Roos C M, Frank D U, Xue C, Johns R A, Rich G F. (1996) Chronic inhaled, nitric oxide: effects on pulmonary vascular endothelial function and pathology in rats. , J Appl Physiol 80(1), 252-60.
  1. 99.BRS Broughton, Walker B R, Resta T C. (2008) Chronic hypoxia induces Rho kinase-dependent mvogenic tone in small pulmonary arteries. , Am J Physiol Lung Cell Mol Physiol 294(4), 797-806.
  1. 100.Cai H, Harrison D G. (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. , Circ Res 87, 840-4.
  1. 101.Li H, Forstermann U. (2000) Nitric oxide in the pathogenesis of vascular disease. , J Pathol 190, 244-54.
  1. 102.Wedgwood S, Bekker J M, Black S M. (2001) Shear stress regulation of endothelial NOS in fetal pulmonary arterial endothelial cells involves PKC. , Am J Physiol Lung Cell Mol Physiol 281, 490-8.
  1. 103.Chatterjee A, Black S M, Catravas J D. (2008) Endothelial nitric oxide (NO) and its pathophysiologic regulation. , Vascul Pharmacol 49, 134-40.
  1. 104.Pagano P J, Clark J K, Cifuentes-Pagano M E, Clark S M, Callis G M. (1997) Localization of a constitutively active, phagocyte-like NADPH oxidase in rabbit aortic adventitia: enhancement by angiotensin II. Proc Natl Acad Sci USA 94, 14483-8.
  1. 105.Liu J Q, Zelko I N, Erbynn E M, Sham J S, Folz R J. (2006) Hypoxic pulmonary hypertension: role of superoxide and NADPH oxidase (gp91phox). , Am J Physiol Lung Cell Mol Physiol 290, 2-10.
  1. 106.Mittal M, Roth M, Konig P, Hofmann S, Dony E. (2007) Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature. Circ Res. 101, 258-67.
  1. 107.Arias-Stella J, Saldana M. (1963) The terminal portion of the pulmonary arterial tree in people native to high altitudes. Circulation . 28, 915-25.
  1. 108.Gupte S A, Wolin M S. (2008) Oxidant and redox signaling in vascular oxygen sensing: implications for systemic and pulmonary hypertension. , Antioxid Redox Signal 10, 1137-1152.
  1. 109.Bärtsch P, JSR Gibbs. (2007) Effect of altitude on the heart and the lungs. , Circulation 116, 2191-2202.
  1. 110.Chaouat A, Naeije R, Weitzenblum E. (2008) Pulmonary hypertension in COPD. , Eur Respir J 32, 1371-85.
  1. 111.Hanna J M. (1999) Climate, altitude and blood pressure. , Hum Biol 71, 553-82.
  1. 112.Prewitt R L, Cardoso S S, Wood W B. (1986) Prevention of arteriolar rarefaction in the spontaneously hypertensive rat by exposure to simulated high altitude. , J Hypertens 4, 735-40.
  1. 113.Tripathy V, Gupta R. (2007) Blood pressure variation among Tibetans at different altitudes. , Ann Human Biol 34, 470-83.
  1. 114.Fiori G, Facchini F, Pettener D, Rimondi A, Battistini N. (2000) Relationships between blood pressure, anthropometric characteristics and blood lipids in high- and low-altitude populations from Central Asia. , Ann Hum Biol 27, 19-28.
  1. 115.Morrell N W, Adnot S, Archer S L, Dupuis J, Jones P L. (2009) Cellular and molecular basis of pulmonary arterial hypertension. , J Am Coll Cardiol. 4:S20-S31
  1. 116.Mazzali M, Jefferson J A, Ni Z, Vaziri N D, Johnson R J. (2003) Microvascular and tubule interstitial injury associated with chronic hypoxia-induced hypertension. , Kidney Int 63, 2088-93.
  1. 117.Jones R, Reid L, Reeves J T, Laurent G J. (1995) Vascular modelling in clinical and experimental pulmonary hypertensions. In Pulmonary Vascular Remodeling. Ed. Bishop JEPortlandPressLtd 47-116.
  1. 118.Simonneau G, Galie N, Rubin L J, Langleben D, Seeger W. (2004) Clinical classification of pulmonary hypertension. , J Am Coll Cardiol 43, 5-12.
  1. 119.Moraes D L, Colucci W S, Givertz M M. (2000) Secondary pulmonary hypertension in chronic heart failure: The role of the endothelium in pathophysiology and management. , Circulation 102, 1718-23.
  1. 120.Penaloza D, Sime F, Banchero N, Gamboa R, Cruz J. (1963) Marticorena E: Pulmonary hypertension in healthy men born and living at high altitudes. Am J Cardiol. , II: 150-157.
  1. 121.JHK Vogel, Weaver W F, Rose R L, Blount SG Jr, Grover R F. (1962) Pulmonary hypertension on exertion in normal man living at 10,150 feet (Leadville, Colorado). Medicina Thoracalis. 19, 461-77.
  1. 122.Stenmark K R, Fagan K A, Frid M G. (2006) Hypoxia-induced pulmonary vascular remodeling cellular and molecular mechanisms. Circ Res. 99, 675-91.
  1. 123.Hislop A, Reid L. (1976) New findings in pulmonary arteries of rats with hypoxia-induced pulmonary hypertension. , Br J Exp Pathol 57, 542-54.
  1. 124.Rabinovitch M, Gamble W, Nadas A S, Miettinen O S, Reid L. (1979) Rat pulmonary circulation after chronic hypoxia: hemodynamic and structural features. , Am J Physiol 236, 818-27.
  1. 125.Heath D. (1996) Pulmonary vascular disease. In Spencer’s pathology of the lung. Ed Hasleton PS. London:McGraw-Hill 649-93.
  1. 126.Tuder R M, Groves B, Badesch D B, Voelkel N F. (1994) Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. , Am J Pathol 144, 275-85.
  1. 127.Hirose S, Hosoda Y, Furuya S, Otsuki T, Ikeda E. (2000) Expression of vascular endothelial growth factor and its receptors correlates closely with formation of the plexiform lesion in human pulmonary hypertension. , Pathol Int 50, 472-9.
  1. 128.Tian H, McKnight S L, Russell D W. (1997) Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. , Genes Dev 11, 72-82.
  1. 129.Makino Y, Cao R, Svensson K, Bertilsson G, Asman M. (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia inducible gene expression. , Nature 414, 550-4.
  1. 130.Yu A Y, Frid M G, Shimoda L A, Wiener C M, Stenmark K. (1998) Temporal , spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. , Am J Physiol 275-818.
  1. 131.Cummins E P, Taylor C T. (2005) Hypoxia-responsive transcription factors. , Pflugers Arch 450, 363-71.
  1. 132.Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y. (1997) A novel bHLHPAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94, 4273-8.
  1. 133.Fukuda R, Hirota K, Fan F, Jung Y D, Ellis L M. (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. , J Biol Chem 277, 38205-11.
  1. 134.Wang G L, Jiang B H, Rue E A, Semenza G L. (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92, 5510-4.
  1. 135.Semenza G L, Agani F, Booth G, Forsythe J, Iyer N. (1997) Structural and functional analysis of hypoxia-inducible factor 1. , Kidney Int 51, 553-5.
  1. 136.Huang L E, Arany Z, Livingston D M, Bunn H F. (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its a subunit. , J Biol Chem 271, 32253-9.