Smooth Muscle Cell Heterogeneity in Proximal Pulmonary Arteries In Vivo Analysis
Although for years investigators had suggested differences between the SMC of large and small vessels, until the 1990's there was limited information regarding the existence of site-specific heterogeneity of SMC within the vascular media. Then, studies in the systemic circulation of experimental animals began to suggest diversity in the SMC composition of large vessel media based on expression patterns of a limited number of contractile and cytoskeletal proteins. There remained, however, a...
Hypoxic Vasoconstriction in Pneumonia
HPV appears to be ineffective in pneumonia. Light et al. measured blood flow with microspheres to the left lower lobe of the dog before and 3 days after inoculating the left lower lobe with Streptococcus pneumoniae 20 . Using radiographs, they confirmed the presence of pneumonia confined to the left lower lobe. Perfusion to the left lower lobe showed a variable and nonsignificant decrease that was not affected by 02 breathing. Utilizing blood samples from the lobar veins at terminal...
Introduction Gmp
Oxygen sensing is a fundamental biological process necessary for the adaptation of living organisms to variable habitats and physiologic situations. In mammals, acute hypoxia triggers fast respiratory and cardiovascular counter-regulatory adjustments to ensure sufficient 02 supply to the most critical organs such as the brain or the heart. Reduction of blood 02 tension Po2 is sensed by the arterial chemoreceptors, which generate afferent chemosensory discharges that activate the brain to evoke...
References Ckb
1. Balasubramaniam V, Le Cras TD, Ivy DD, Grover T R, Kinsella JP, and Abman SH. Role of platelet derived growth factor in vascular remodeling during pulmonary hypertension in the ovine fetus. Am. J. Physiol. Lung Cell. Mol. Physiol. 2003 184 L826-L833. 2. Blumberg FC, Lorenz C, Wolf K, Sandner P, Riegger GA, and Pfeifer M. Increased pulmonary prostacyclin synthesis in rats with chronic hypoxic pulmonary hypertension. 3. Christou H, Yoshida A, Arthur V, Morita T, and Kourembanas S. Increased...
Vitamin C
Vitamin C ascorbate is a water soluble vitamin present in the cytosol and extracellular fluid. It can interact directly with superoxide and hydroxyl radical. In addition, vitamin C can also donate an electron to the vitamin E radical. It is then oxidized to a semidehydroascorbate SDA radical. SDA is recycled by i dihydrolipoate or ii disproportionate reaction forming dehydroascorbate DHA . In the presence of GSH, DHA reductase catalyzes the regeneration of ascorbate. Alternatively, SDA can be...
Conclusions
Currently, there are several proposed mechanisms of oxygen sensing in pulmonary artery smooth muscle cells. Most of the models are related to either increases or decreases in reactive oxygen species. Discrepancies among investigators are likely related to differences in preparations and detection methods of detecting ROS. Furthermore, the source of ROS generation has been proposed as either the mitochondrial electron transport chain or NADPH oxidase. Our own observations suggest that a similar...
Mitochondrial Function and Responsiveness to Hypoxia of Glomus Cells
Despite the progress in the understanding of glomus cell electrophysiology and its responses to hypoxia, how 02 is sensed in the carotid body remains unknown. It has been reported that modulation of some K channels by Po2 in glomus cells is maintained in excised patches, thus suggesting that 02 sensing depends on membrane-delimited mechanisms 11, 18, 19, 35 . On the other hand, mitochondria have traditionally been considered as the site for glomus cell 02 sensing by several investigators...
Selective Block of Phase 1 of Hypoxic Pulmonary Vasoconstriction in Isolated
Many studies have shown that phase 1 of HPV may be inhibited by Ca2 channel blockers 11, 32,42,58 , or by depletion of ryanodine-sensitive SRCa2 stores 12,13, 23, 29, 58 . More recently, it has been proposed that inhibition of SR Ca2 ATPase activity 12, 52 and subsequent activation of Ca2 entry via a store-refilling current may underpin phase 1 of HPV 52 . Our investigations proved to be consistent with all of the above except for a role for Ca2 entry via a store-refilling current. As mentioned...
Unanswered Questions
a Based on knowledge derived from human and animal disease models, are PASMC a case of congenital proximal ETC deficiency The difference between PA and RA mitochondria is analogous to the comparison of mitochondria from healthy subjects versus patients with ETC complex I deficiency. Fibroblasts from complex I deficient patients have increased mitochondria-derived AOS production compared with controls 7, 45 . In addition, their fibroblasts exhibit impaired mitochondrial function, as reflected by...
Intracellular Ca2 Indicators
Most Ca2 -sensitive fluorescent indicators are variants of the Ca2 chelators acid BAPTA and ethylene glycol-bis p-aminoethyl ether -N,N,N',N'-tetraacetic acid EGTA 2,12 . These fluorophores vary mainly in terms of their excitation and emission wavelengths and their Ca2 dissociation constants Kd . A number of factors must be taken into account when selecting an indicator, i Many commercially available intracellular Ca2 indicators are available in free salt, AM ester, and dextran forms, thereby...
Diffuse Alveolar Hypoxia
Operation Everest II in 1985 involved 8 male athletes who were decompressed in a hypoxic chamber for 40 days to a barometric pressure of 240 Torr 11 . The application of diffuse hypoxia 9.5 02 to the lungs of these atheletes caused a rise in pulmonary artery pressure acutely from 15 1 to 20 2 mmHg P lt 0.05 . Pulmonary capillary wedge pressure rose from 7 1 to 9 1 mmHg which was statistically insignificant. However, cardiac output rose from 6.7 0.4 to 8.1 0.7 L min P lt 0.05 . Thus pulmonary...
Conclusion Ffp
The role of growth factors in HPH is an open book, with no ending in sight. As novel vascular growth factors are discovered, and as we learn more about their biological and pathobiological role, we add a new level of understanding in HPH. Undoubtedly, abnormal vascular cell growth is at the center of pulmonary vascular remodeling in pulmonary hypertension Fig. 3 . In the next few years, the elucidation of master control levels of pulmonary vascular remodeling using genomics and proteonomics of...
Role of Cytochrome c Oxidase as an Electron Transport Chain Heme Protein in 02
Since a decrease in cytochrome c oxidase enzyme activity can be observed at Po2 levels below 2 to 3 mm Hg, it was proposed that this enzyme acts as an 02 sensor 13 . Studies in embryonic cardiomyocytes showed that, under decreasing Po2 15 to 1 02 , an increased oxidation of the non-fluorescent 2',7-dichlorofluorescin DCFH to the fluorescent DCF, an indicator of ROS presence, occurred 17 . Paradoxically, upon return to normoxia, DCF fluorescence decreased again 17 . Similar to cardiomyocytes,...
Increased Glucose Uptake and Acceleration of Glycolysis
Investigations into the effect of hypoxia on skeletal muscle have demonstrated that glucose uptake is increased and glycolysis accelerated 14 . There is also evidence to suggest that active glucose uptake is facilitated and glycolysis accelerated by hypoxia in pulmonary artery smooth muscle and or endothelial cells 52, 54 . This is not surprising, since glycolysis is rate-determined by glucose uptake in the lung 70 . In bladder smooth muscle, it was reported that at least 60 of ATP production...
Is AMPactivated Protein Kinase the Metabolic Sensor and Primary Effector in
Given that hypoxia likely triggers an increase in cellular AMP levels, it seems possible that the AMP-activated protein kinase AMPK may play a role in regulating the activity of 02-sensing cells. AMPK is a multi-substrate serine threonine kinase, which acts as a metabolic sensor and modulates many aspects of cell metabolism in eukaryotes 37,47 . AMPK effectively detects metabolic stress through changes in the local ATP AMP ratio, and may be activated by vigorous exercise, nutrient starvation...
Diversity of Mitochondrial among Organs Evidence from Metabolic Pathways
It has been well-known that some organ-specific metabolic pathways represent good examples of mitochondrial diversity 33 . Synthesis of carbamoyl-phosphate and citrulline, first two steps of urea synthesis, is located only within liver mitochondria. A liver-specific ornithine-citrulline antiporter is responsible for the import of ornithine into, and the export of citrulline out of the liver mitochondria 33 . Gluconeogenesis is a liver- and kidney-specific pathway. The formation of oxaloacetate...
Microdomains and Organized Signaling in Regulating Kv Channel Function in PASMC
An emerging idea in signal transduction posits the existence of spatially organized complexes of signaling molecules in microdomains 62, 65 of the plasma membrane. Recent studies have focused on the distribution of signaling molecules in caveolae, which are cholesterol and sphingolipid-enriched regions that can form distinct structural invaginations of the plasma membrane and are enriched of the protein caveolin 97 . This notion of signaling microdomains is attractive in that it would account...
Transgenic Mouse Models in Research on Hypoxic Pulmonary Hypertension
During the past few years, many transgenic mouse lines have been established for research on hypoxic pulmonary hypertension 6, 17, 19, 29 . Studies with these mice have provided significant insights into the pathogenesis and potential treatment of hypoxia-induced pulmonary hypertension. Patients with severe pulmonary hypertension have low levels ofprostacyclin synthase PGIS 3 , but the pathogenic significance ofthis deficiency is unclear. Recently, transgenic mice overexpressing PGIS...
Role of Increased ET1 and 5HT in Hypoxic Pulmonary Hypertension
Although several different vasoconstrictors are implicated in the complex pathophysiology of HPH, it is evident that ET-1 and 5-HT play major roles in the vasoconstriction and vascular remodeling 6, 11, 28 . ET-1 is a pulmonary vasoconstrictor and co-mitogen, and either selective ETA or mixed ETA ETB receptor blockade attenuates HPH in rats. ET-l-induced vasoconstriction is mediated through activation of smooth muscle cell ETA and ETB receptors, and is moderated by endothelial cell ETB...
References Pkd
1. Abman SH, and Accurso FJ. Acute effects of partial compression of the ductus arteriosus on the fetal pulmonary circulation. Am. J. Physiol. 1989 257 H626-H634. 2. Abman SH, and Accurso FJ. Sustained fetal pulmonary vasodilation during prolonged infusion of atrial natriuretic factor and 8-bromo-guanosine monophosphate. Am. J. Physiol. 1991 260 H183-H192. 3. Abman SH, Chatfield BA, Hall SL, and McMurtry IF. Role of endothelium-derived relaxing factor during transition ofpulmonary circulation...
The Role of Microcirculation in Hypoxic Pulmonary Hypertension
The role of the capillary blood vessels of the lung in HPH is to reduce the resistance to flow in pulmonary microcirculation. The reason that these vessels can do it is because of their geometry. When the pulmonary capillary blood vessels of cat were photographed on face, they appeared as shown in Figure 1 A. When these capillary vessels were photographed in cross section, they appear as shown in Figure IB. From these photographs one sees that the capillaries form sheets of blood space that are...
Hypoxia Augments Mitochondrial Reactive Oxygen Species
During mitochondrial respiration under normal oxygen conditions, 02 is chemically reduced to water by the transfer of four electrons at cytochrome oxidase. The resulting free energy change is conserved in the form of ATP synthesis. It has been estimated that 2-3 ofthe 02 consumed by mitochondria is incompletely reduced, yielding ROS 4 . Univalent electron transfer to 02 generates superoxide, a modestly stable free radical anion. Superoxide can potentially be generated at a number of different...
Physiologic Characteristics of Hypoxic Pulmonary Vasoconstriction
In humans and adult animals the alveolar oxygen tension Po2 needs to reach 60 mmHg or lower to initiate pulmonary vasoconstriction 5, 26 . In newborn sheep, however, there is evidence of active hypoxic tone even when being ventilated with 30 F,02 5 . This enhanced sensitivity to alveolar hypoxia in the newborn probably accounts for the well-known flip flop of the circulation in the newborn when weaning from the ventilator during which suddenly pulmonary vascular resistance is high and the fetal...
Role of Deficient NO and PGI2 in Hypoxic Pulmonary Hypertension
Endogenous NO, derived largely from eNOS, is a potent inhibitor of pulmonary vasoconstriction and HPH 15 . Although eNOS is moderately upregulated in hypoxic hypertensive lungs, and NO suppresses an increased endogenous ET-1-mediated pulmonary vasoconstriction 41, 46, 48 , hypoxic ventilation limits lung NO production 53 . Therefore, deficient production of NO likely plays a role in the development of HPH. Chronic inhaled NO inhibits HPH, and transgenic eNOS-overexpressing mice have increased...
Generation of Transgenic Mice
2.1. Application of Transgenic Mouse Technology Transgenic mice are widely used in biomedical research, and numerous applications have been developed, including those used in hypoxic pulmonary hypertension 5, 6, 19, 29 . There are two common uses of transgenic mice in biomedical research. The first is to study the phenotypic effects of transgene expression in the intact animal. In this case, previously defined promoters are often used to control the expression of the transgene in the desired...
Response of the Intima Media and Adventitia to Hypoxia
Within the pulmonary vasculature there are three major cell types each predominating in their own layer, but intimately associated with the others endothelial cells intima , smooth muscle cells media , and fibroblasts adventitia . While the vascular remodeling generally consists of smooth muscle cell hypertrophy hyperplasia and smooth muscle cell migration into the smaller arterioles, all cell layers affect this process. Endothelial cells form the interface between the blood and the underlying...
Acute Hypoxia Induces Membrane Depolarization by Inhibiting Kv Channels
In rat PASMC, acute hypoxia reduces K currents by inhibiting Kv channels Fig. 4Ca 5, 63, 82, 83, 117 . The inhibitory effect of hypoxia on Kv channels appears to be selective to PASMC hypoxia has little effect on Kv currents K V in mesenteric artery smooth muscle cells MASMC isolated from the same rat Fig. 4Cb . The inability of acute hypoxia to reduce K V in MASMC also explains why acute hypoxia has little effect on mesenteric vascular tone 120 . The acute hypoxia-mediated inhibition of Kv...
Oxygen Sensitivity of PC12 Cells
An initial critical step in the process of 02-sensing common to chemosensitive cells is membrane depolarization upon exposure to hypoxia 21, 22 . This event is essential for activating voltage-sensitive Ca2 channels and producing the increase in Ca2 , necessary to trigger many physiological responses such as constriction in pulmonary artery and neurotransmitter release in CB . Like other oxygen-chemosensitive cells, PC12 cells respond to acute exposure to hypoxia with membrane depolarization....
Role of Protein Tyrosine Kinases PTKs
PTKs are usually associated with growth factor linked receptors and play pivotal roles in many cell-signaling processes 13 . PTK activation has been associated with an increase in Ca2 -sensitivity in smooth muscle 51 and evidence for involvement ofPTKs in HPV has been found in sheep 53 and rat isolated pulmonary arteries 56 . The evidence for the involvement of PTK activation in HPV is based upon the inhibitory effects of PTK antagonists, such as genistein and the tyrphostins, and the...
Store DepletionActivated Channels in Pulmonary Artery Smooth Muscle
Little is known yet about the ion channels mediating CCE in pulmonary artery smooth muscle. Store depletion-activated cation currents recorded from rat pulmonary artery myocytes Fig. ID have amplitudes of only a few pA in the presence of physiological levels of Ca2 27 . Store operated currents of similarly small amplitude have been recorded from rabbit and mouse arterial 5, 39 and rabbit venous 1, 20 smooth muscle cells. In contrast, large currents of several hundred pA were reported in...
Heterogeneity in the Modulation of HPV
HPV in response to a decrease in pulmonary arterial P02 raises one of the potential risks associated with local V Q control based on constriction of pulmonary arteries in response to low Po2 namely, that of maintaining a low pulmonary vascular resistance during exercise. Part of the increase in oxygen consumption associated with exercise is accommodated by increased oxygen extraction by the working muscles, the result being a decrease in mixed venous P02. For example, in human subjects...
Mitochondria as Oxygen Sensors
The mitochondrion's role as the predominant site for 02 consumption and ATP synthesis makes it an obvious candidate site for an 02 sensor. The finding that inhibition of the mitochondrial electron transport chain ETC mimics hypoxia further supports this hypothesis 4 . Indeed ETC inhibitors cause pulmonary vasoconstriction, systemic vasodilation and carotid body activation, a set of responses elicited by few other stimuli save hypoxia 4 . Figure 4 Mitochondria regulate K channel function through...
Variability of Pulmonary Vascular Remodeling Among Species and Individuals The
Acute hypoxic pulmonary vasoconstriction is ubiquitous among adult mammals, but considerable variations in chronic hypoxic PH occur within and across species 27 . During chronic exposure to high altitude, PH is more severe in cattle and horses than in sheep and dogs. Furthermore, among humans and other mammals that live at high altitudes for many generations, PH is less severe and shows less inter-individual variation than in subjects from low altitudes that are briefly exposed to high...
K Channel Expression is Regulated by Auxiliary Regulatory Proteins
An emerging idea in the area of regulation of fonction and expression of Kv channels is the direct interaction of the pore-forming a subunits with K channel-associated proteins KChAPs and K channel-interacting proteins KChlPs , regulators different from the Kv channel P subunits. These proteins have predominantly been described in the brain and heart and play an important role in regulating Kv channel function and expression in these tissues little data exist regarding their role on channel...
Inhibition of cADPRdependent Dilation by Hypoxia
Cyclopiazonic acid inhibits phase 1 of HPV without any effect on maintained constriction by hypoxia. We mentioned at the time that cyclopiazonic acid may act to deplete a Ca2 store that is functionally discrete from that which serves cADPR-dependent SR Ca2 release by hypoxia. Our most recent investigations provide strong support for this conclusion. We have demonstrated that cADPR mediates, in part, vasodilation by adenylyl cyclase-coupled receptors, such as P-adrenoceptors, by releasing Ca2...
Sensors Mediators and Modulators
Subsequent studies in cat small pulmonary artery smooth muscle cells, showed that intracellular Ca2 increased during hypoxia but decreased in cells from large pulmonary and cerebral arteries 55 . The Ca2 increase was due to Ca2 release from ryanodine-sensitive intracellular stores and Ca2 influx from the extracellular fluid. Patch-clamping and immunofluorescent microscopy combined with ever more selective pharmacologic agents further elucidated the roles of Ca2 , K , and other ions in...
Implications of Ca2 Sparks for Hypoxic Pulmonary Vasoconstriction
Even though there are still uncertainties on whether Ca2 release is an early event in HPV, it is rather clear that RyR-gated Ca2 stores play a central role in the process. Inhibition of RyRs has been shown to completely abolish or to partially inhibit hypoxia-induced Ca2 responses in PASMCs 15, 49 and hypoxia-induced vasoconstriction in isolated perfused lung 31 , pulmonary arteries 18, 25 . Recently, some have proposed that hypoxia causes a change in the cellular redox-state, in particular a...
Molecular Properties of Ko2 Channels in PC 12 Cells
Further molecular biological experiments have indicated that the Ko2 channel in PC 12 cells belongs to the KV1 subfamily 6, 7 . Kv channels are tetrameric arrangements of 4 separate pore-forming a subunits and auxiliary P subunits 5 . The genes that encode functional Kv a subunits are classified in 4 major subfamilies Kvl-Kv4. New subfamilies Kv5.1-Kv10 are recently added. The molecular composition of Ko2 channels is still under investigation. The Kv a subunits implicated informing Ko2 channels...
Kluwer Academic Publishers
NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW eBook ISBN 1-4020-7858-7 Print ISBN 1-4020-7857-9 New York, Boston, Dordrecht, London, Moscow Print 2004 Kluwer Academic Publishers Boston No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at and Kluwer's eBookstore at http kluweronline.com http ebooks.kluweronline.com...
Complex I NADH Ubiquinone Oxidoreductase
During oxidative phosphorylation, electrons pass through a series of membrane-bound multiprotein complexes that translocate protons across the membrane, resulting in a proton-motive force used by ATP synthase to make ATP 1 . It couples the transfer of two electrons from NADH to ubiquinone to the translocation of four protons across the inner mitochondrial membrane. Complex I is the first of these electron transfer complexes and accounts for up to 40 of the pumped protons 50 . In human...
Oxidative Phosphorylation by Mitochondria
Oxidative phosphorylation by mitochondria is driven, in part, by acetyl CoA, which is derived from pyruvate Fig. 2 . Acetyl CoA enters the Krebs cycle where cycles of substrate dehydrogenation lead to the reduction of P-NAD to P-NADH. Together with P-NADH derived from glycolysis, this provides electrons and protons for the electron transport chain ETC on oxidation of P-NADH at complex I. In addition, FADH2, produced by succinate dehydrogenase, provides electrons and protons for the ETC upon...
Treatment of PPHN
In general, management of the newborn with PPHN includes the treatment and avoidance of hypothermia, hypoglycemia, hypocalcemia, anemia and hypovolemia correction of metabolic acidosis diagnostic studies for sepsis serial monitoring of arterial blood pressure, pulse oximetery pre- and post-ductal and transcutaneous PCo2, especially with the initiation of high frequency oscillatory ventilation HFOV . Therapy includes aggressive management of systemic hemodynamics with volume and cardiotonic...
References Tku
1. Alcayaga J, Iturriaga R, and Zapata P. Time structure, temporal correlation and coherence of chemosensory impulses propagated through both carotid nerves of the cat. Bio. Res. 1997 30 125-133. 2. Aaronson PI, Robertson TP, and Ward JPT. Endothelium-derived mediators and hypoxic pulmonary vasoconstriction. Resp. Physiol. Neurobiol. 2002 132 107-120. 3. Adriaensen D, and Scheuermann D. Neuroendocrine cells and nerves of the lung. Anatomical Record. 1993 236 70-85. 4. Annex BH, and Williams RS....
Pheochromocytoma PC12 Cells
The PC12 clonal cells were originally derived from rat adrenal medullary tumors 12 . These cells synthesize catecholamines in particular dopamine and norepinephrine and release them in response to a variety of stimuli 12 . Although this cell line has been widely used as a model system for neurobiological and neurochemical studies, in the past ten years, PC 12 cells have proven to be an important tool in better understanding the different aspects of 02-sensing. The interest in PC12 cells as...
Redox Regulation of Ca2 Release from Sarcoplasmic Reticulum
Several studies on the redox regulation of the SR Ca2 -release channel complex, consisting of the RyR, the FK506 binding protein and other associated proteins and molecules such as junctin, triadin and calmodulin, have been conducted on skeletal and cardiac muscle cells. Feng et al. have provided direct evidence that ryanodine channel activity follows transmembrane redox potential 28 . The molecular basis of 02-responsiveness in these cells was identified to involve 6-8 of 50 RyR thiols whose...
H H202 02[26
SOD provides the first line of enzymatic defense against intracellular free radical production by removing 02' There are three types of SOD copper zinc SOD Cu Zn SOD, SOD1 , manganese SOD Mn SOD, SOD2 , and extracellular SOD EC-SOD, SOD 3 . Cu Zn-SOD is a highly stable enzyme found in the cytosol and nucleus of all cell types 8 . It is dimer composed of two 16 kDa subunits, each containing 1 copper and 1 zinc atom. The copper is essential for the enzyme's catalytic activity while the zinc...
References Gco
1. Anger M, Lompre A-M, Vallot O, Marotte F, Rappaport L, and Samuel J-L. Cellular distribution of Ca2 pumps and Ca2 release channels in rat cardiac hypertrophy induced by aortic stenosis. Circulation. 1998 98 2477-2486. 2. Aguirre JI, Morrell NW, Long L, Clift P, Upton PD, Polak JM, and Wilkins MR. Vascular remodeling and ET-1 expression in rat strains with different responses to chronic hypoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000 278 L981-L987. 3. Barnes PJ and Liu SF. Regulation...
Ryanodine Receptors Ca2 Channels and Ca2 Sparks in Pulmonary Artery Smooth
In pulmonary arteries, the expression of RyR subtypes has not been reported. Ongoing studies in our laboratory detected mRNA for all three RyR subtypes using reverse-transcription polymerase chain reaction, and RyR1 and RyR2 proteins by Western blot and immunostaining techniques Yang and Sham, unpublished data , suggesting that multiple RyR subtypes are expressed in rat PASMCs as in systemic myocytes 11, 27, 30, 34 . Even though it is unclear which RyR subtype is the major contributor for spark...
Transgenic Animal Models
Mice and rats in which specific genes are either under or overexpressed are increasingly being used to study mechanisms of HPV. For example, HPV is impaired in mice lacking certain Kv channels 3 and increased in rats lacking the ETb receptor 21 . Genetically altered animals would thus appear to offer the best of all worlds, a particular mechanism can be eliminated or elaborated and the result can be studied in the whole animal, its organs, its tissues, and its cells. However, it should be noted...
Transcriptional Responses to Hypoxia
Hypoxia has been shown to affect the expression of specific genes by modulating a variety of transcription factors and transduction-signaling proteins. An essential mediator of transcriptional responses to decreased 02 availability is hypoxia-inducible factor 1 HIF-1 . Many genes implicated in the development of polycythemia and chronic hypoxic PH erythropoietin, transferrin, vascular endothelial growth factor VEGF , VEGF receptor 1, iNOS, heme oxygenase-1, ET-1, and 5-HTT contain functionally...