Skip to main content
SpringerLink
Log in

Rho/Rho-kinase Signaling in Hypoxic Pulmonary Hypertension

  • Chapter
Hypoxic Pulmonary Vasoconstriction

Part of the book series: Developments in Cardiovascular Medicine ((DICM,volume 252))

  • 118 Accesses

Summary

The small GTPase RhoA and its downstream effector Rho-kinase play a role in many cellular functions including cell adhesion, migration, gene expression, growth, and contraction. Rho/Rho-kinase signaling can promote sustained increases in vascular tone by both increasing the Ca2+ sensitivity of vascular smooth muscle cell contraction and downregulating expression of vasodilators and upregulating expression of vasoconstrictors. There is considerable evidence that Rho/Rho-kinase activation is important in the pathogenesis of systemic vascular diseases such as hypertension, vasospasm, and arteriosclerosis. It is therefore reasonable to hypothesize that this signaling pathway also contributes to the pathogenesis of hypoxia-mediated pulmonary hypertension by promoting sustained pulmonary vasoconstriction and vascular wall remodeling. Our observations that an inhibitor of Rho-kinase effectively reverses high pulmonary vascular resistance in chronically hypoxic rats and blunts development of hypoxic pulmonary hypertension in rats and mice support this concept. It is now apparent that Rho/Rho-kinase signaling needs to be added to the blend of increased cytosolic [Ca2+] and sundry other signaling molecules and pathways to fully understand the molecular pathophysiology of hypoxia-induced pulmonary hypertension.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abe K, Shimokawa H, Uwatoku T, Matsumoto Y, and Hattori T. Long-term inhibition of Rho-kinase markedly ameliorates monocrotaline-induced pulmonary hypertension in rats. Circulation. 2002; 106: II-365.

    Google Scholar 

  2. Abe Y, Tatsumi K, Sugito K, Ikeda Y, Kimura H, and Kuriyama T. Effects of inhaled prostacyclin analogue on chronic hypoxic pulmonary hypertension. J. Cardiovasc. Pharmacol. 2001; 37: 239–251.

    Article  CAS  PubMed  Google Scholar 

  3. Bishop AL, and Hall A. Rho GTPases and their effector proteins. Biochem. J. 2000; 348: 241–255.

    Article  CAS  PubMed  Google Scholar 

  4. Carvajal JA, Germain AM, Huidobro-Toro JP, and Weiner CP. Molecular mechanism of cGMP-mediated smooth muscle relaxation. J. Cell. Physiol. 2000; 184: 409–420.

    Article  CAS  PubMed  Google Scholar 

  5. Cattaruzza M, Eberhardt I, and Hecker M. Mechanosensitive transcription factors involved in endothelin B receptor expression. J. Biol. Chem. 2001; 276: 36999–37003.

    Article  CAS  PubMed  Google Scholar 

  6. Chen YF and Oparil S. Endothelin and pulmonary hypertension. J. Cardiovasc. Pharmacol. 2000; 35: S49–53.

    Google Scholar 

  7. Chida M and Voelkel NF. Effects of acute and chronic hypoxia on rat lung cyclooxygenase. Am. J. Physiol. 1996; 270: L872–L878.

    CAS  PubMed  Google Scholar 

  8. Damron DS, Kanaya N, Homma Y, Kim SO, and Murray PA. Role of PKC, tyrosine kinases, and Rho kinase in alpha-adrenoreceptor-mediated PASM contraction. Am. J. Physiol. Lung Cell. Mol. Physiol. 2002; 283: L1051–L1064.

    CAS  PubMed  Google Scholar 

  9. Davie N, Haleen SJ, Upton PD, Polak JM, Yacoub MH, Morrell NW, and Wharton J. ET A and ET B receptors modulate the proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Crit. Care Med. 2002; 165: 398–405.

    PubMed  Google Scholar 

  10. Degraeve F, Bolla M, Blaie S, Creminon C, Quere I, Boquet P, Levy-Toledano S, Bertoglio J, and Habib A. Modulation of COX-2 expression by statins in human aortic smooth muscle cells. Involvement of geranylgeranylated proteins. J. Biol. Chem. 2001; 276: 46849–46855.

    Article  CAS  PubMed  Google Scholar 

  11. Eddahibi S, Raffestin B, Hamon M, and Adnot S. Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension? J. Lab. Clin. Med. 2002; 139: 194–201.

    Article  CAS  PubMed  Google Scholar 

  12. Eto M, Barandier C, Rathgeb L, Kozai T, Joch H, Yang Z, and Luscher TF. Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-activated protein kinase. Circ. Res. 2001; 89: 583–590.

    CAS  PubMed  Google Scholar 

  13. Etter EF, Eto M, Wardle RL, Brautigan DL, and Murphy RA. Activation of myosin light chain phosphatase in intact arterial smooth muscle during nitric oxide-induced relaxation. J. Biol. Chem. 2001; 276: 34681–34685.

    Article  CAS  PubMed  Google Scholar 

  14. Evans AM, Cobban HJ, and Nixon GF. ET A receptors are the primary mediators of myofilament calcium sensitization induced by ET-1 in rat pulmonary artery smooth muscle: a tyrosine kinase independent pathway. Br. J. Pharmacol. 1999; 127: 153–160.

    CAS  PubMed  Google Scholar 

  15. Fagan KA, McMurtry I, and Rodman DM. Nitric oxide synthase in pulmonary hypertension: lessons from knockout mice. Physiol. Res. 2000; 49: 539–548.

    CAS  PubMed  Google Scholar 

  16. Fagan KA, Oka M, and McMurtry IF. Rho-kinase inhibitor (Y27632) attenuates the development of hypoxia-induced pulmonary hypertension in mice. Am. J. Respir. Cell. Mol. Biol. 2002; 165: B53.

    Google Scholar 

  17. Geraci MW, Gao B, Shepherd DC, Moore MD, Westcott JY, Fagan KA, Alger LA, Tuder RM, and Voelkel NF. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension. J. Clin. Invest. 1999; 103: 1509–1515.

    CAS  PubMed  Google Scholar 

  18. Girgis RE, Li D, Tuder RM, Johns RA, and Garcia JGN. Attenuation of hypoxic pulmonary hypertension in rats by the HMG-CoA reductase inhibitor, simvastatin. J. Heart Lung Transpl. 2002; 21: 149.

    Google Scholar 

  19. Gohla A, Schultz G, and Offermanns S. Role for G12/G13 in agonist-induced vascular smooth muscle cell contraction. Circ. Res. 2000; 87: 221–227.

    CAS  PubMed  Google Scholar 

  20. Halayko AJ and Solway J. Molecular mechanisms of phenotypic plasticity in smooth muscle cells. J. Appl. Physiol. 2001; 90: 358–368.

    CAS  PubMed  Google Scholar 

  21. Hernandez-Perera O, Perez-Sala D, Soria E, and Lamas S. Involvement of Rho GTPases in the transcriptional inhibition of preproendothelin-1 gene expression by simvastatin in vascular endothelial cells. Circ. Res. 2000; 87: 616–622.

    CAS  PubMed  Google Scholar 

  22. Hongo M, Hironaka E, Sakai A, Yazaki Y, Kinoshita O, and Owa M. Pravastatin improves monocrotaline-induced pulmonary hypertension and prolongs survival in rats independent of cholesterol lowering. Circulation. 2002; 106: II-366.

    Google Scholar 

  23. Hoshikawa Y, Voelkel NF, Gesell TL, Moore MD, Morris KG, Alger LA, Narumiya S, and Geraci MW. Prostacyclin receptor-dependent modulation of pulmonary vascular remodeling. Am. J. Respir. Crit. Care Med. 2001; 164: 314–318.

    CAS  PubMed  Google Scholar 

  24. Ichiki T, Takeda K, Tokunou T, Iino N, Egashira K, Shimokawa H, Hirano K, Kanaide H, and Takeshita A. Downregulation of angiotensin II type 1 receptor by hydrophobic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1896–1901.

    CAS  PubMed  Google Scholar 

  25. Ivy DD, Yanagisawa M, Gariepy CE, Gebb SA, Colvin KL, and McMurtry IF. Exaggerated hypoxic pulmonary hypertension in endothelin B receptor-deficient rats. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2002; 282: L703–L712.

    CAS  PubMed  Google Scholar 

  26. Janssen LJ, Lu-Chao H, and Netherton S. Excitation-contraction coupling in pulmonary vascular smooth muscle involves tyrosine kinase and Rho kinase. Am. J. Physiol. Lung Cell. Mol. Physiol. 2001; 280: L666–L674.

    CAS  PubMed  Google Scholar 

  27. Janssen LJ, Premji M, Netherton S, Coruzzi J, Lu-Chao H, and Cox PG. Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinase in human and canine pulmonary vascular smooth muscles. Br. J. Pharmacol. 2001; 132: 127–134.

    Article  CAS  PubMed  Google Scholar 

  28. Jeffery TK, and Wanstall JC. Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension. Pharmacol. Ther. 2001; 92: 1–20.

    Article  CAS  PubMed  Google Scholar 

  29. Kataoka C, Egashira K, Inoue S, Takemoto M, Ni W, Koyanagi M, Kitamoto S, Usui M, Kaibuchi K, Shimokawa H, and Takeshita A. Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 2002; 39: 245–250.

    Article  CAS  PubMed  Google Scholar 

  30. Keegan A, Morecroft I, Smillie D, Hicks MN, and MacLean MR. Contribution of the 5-HT1B receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT1B-receptor knockout mice and the 5-HT1B/1D-receptor antagonist GR127935. Circ. Res. 2001; 89: 1231–1239.

    CAS  PubMed  Google Scholar 

  31. Laufs U, and Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J. Biol. Chem. 1998; 273: 24266–24271.

    Article  CAS  PubMed  Google Scholar 

  32. Laufs U, Marra D, Node K, and Liao JK. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J. Biol. Chem. 1999; 274: 21926–21931.

    Article  CAS  PubMed  Google Scholar 

  33. Launay J-M, Herve P, Peoc’h K, Tournois C, Callebert J, Nebigil CG, Etienne N, Drouet L, Humbert M, Simonneau G, and Maroteaux L. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nat. Med. 2002; 8: 1129–1135.

    Article  CAS  PubMed  Google Scholar 

  34. Lee SL, Simon AR, Wang WW, and Fanburg BL. H2O2 signals 5-HT-induced ERK MAP kinase activation and mitogenesis of smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 2001; 281: L646–L652.

    CAS  PubMed  Google Scholar 

  35. MacLean MR, and Morecroft I. Increased contractile response to 5-hydroxytryptamine1-receptor stimulation in pulmonary arteries from chronic hypoxic rats: role of pharmacological synergy. Br. J. Pharmacol. 2001; 134: 614–620.

    Article  CAS  PubMed  Google Scholar 

  36. Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, and Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002; 105: 1545–1547.

    Article  CAS  PubMed  Google Scholar 

  37. Morio Y, Oka M, and McMurtry IF. A selective Rho-kinase inhibitor, Y-27632, is an effective vasodilator of chronically hypoxic hypertensive rat lungs. FASEB J. 2002; 16: A74.

    Google Scholar 

  38. Morishige K, Shimokawa H, Eto Y, Kandabashi T, Miyata K, Matsumoto Y, Hoshijima M, Kaibuchi K, and Takeshita A. Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 548–554.

    CAS  PubMed  Google Scholar 

  39. Mukai Y, Shimokawa H, Matoba T, Kandabashi T, Satoh S, Hiroki J, Kaibuchi K, and Takeshita A. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 2001; 15: 1062–1064.

    CAS  PubMed  Google Scholar 

  40. Muniyappa R, Xu R, Ram JL, and Sowers JR. Inhibition of Rho protein stimulates iNOS expression in rat vascular smooth muscle cells. Am. J. Physiol. Heart Circ. Physiol. 2000; 278: H1762–H1768.

    CAS  PubMed  Google Scholar 

  41. Muramatsu M, Rodman DM, Oka M, and McMurtry IF. Endothelin-1 mediates nitro-Larginine vasoconstriction of hypertensive rat lungs. Am. J. Physiol. 1997; 272: L807–L812.

    CAS  PubMed  Google Scholar 

  42. Nagaoka T, Morio Y, Oka M, and Mcmurtry IF. Endothelin-1 and serotonin are involved in Rho-kinase-mediated augmented pressor response to KCl in chronically hypoxic hypertensive rat lungs. Am. J. Respir. Cell. Mol. Biol. 2003; 167:A697.

    Google Scholar 

  43. Niiro N, Koga Y, and Ikebe M. Agonist-induced changes in the phosphorylation of the myosin-binding subunit of myosin light chain phosphatase and CPI17, two regulatory factors of myosin light chain phosphatase, in smooth muscle. Biochem. J. 2003; 369: 117–128.

    Article  CAS  PubMed  Google Scholar 

  44. Nishimura T, Faul JL, Berry GJ, Vaszar LT, Qiu D, Pearl RG, and Kao PN. Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am. J. Respir. Crit. Care Med. 2002; 166: 1403–1408.

    Article  PubMed  Google Scholar 

  45. Numaguchi K, Eguchi S, Yamakawa T, Motley ED, and Inagami T. Mechanotransduction of rat aortic vascular smooth muscle cells requires RhoA and intact actin filaments. Circ. Res. 1999; 85: 5–11.

    CAS  PubMed  Google Scholar 

  46. Oka M, Hasunuma K, Webb SA, Stelzner TJ, Rodman DM, and McMurtry IF. EDRF suppresses an unidentified vasoconstrictor mechanism in hypertensive rat lungs. Am. J. Physiol. 1993; 264: L587–L597.

    CAS  PubMed  Google Scholar 

  47. Oka M, Morio Y, Morris KG, and McMurtry I. Acute hemodynamic effects of Y27632, a selective Rho-kinase inhibitor, in chronically hypoxic pulmonary hypertensive rats. FASEB J. 2002; 16: A74.

    Google Scholar 

  48. Oka M, Morris KG, and McMurtry IF. NIP-121 is more effective than nifedipine in acutely reversing chronic pulmonary hypertension. J. Appl. Physiol. 1993; 75: 1075–1080.

    CAS  PubMed  Google Scholar 

  49. Ozaki M, Kawashima S, Yamashita T, Ohashi Y, Rikitake Y, Inoue N, Hirata KI, Hayashi Y, Itoh H, and Yokoyama M. Reduced hypoxic pulmonary vascular remodeling by nitric oxide from the endothelium. Hypertension. 2001; 37: 322–327.

    CAS  PubMed  Google Scholar 

  50. Robertson TP, Dipp M, Ward JP, Aaronson PI, and Evans AM. Inhibition of sustained hypoxic vasoconstriction by Y-27632 in isolated intrapulmonary arteries and perfused lung of the rat. Br. J. Pharmacol. 2000; 131: 5–9.

    Article  CAS  PubMed  Google Scholar 

  51. Sah VP, Seasholtz TM, Sagi SA, and Brown JH. The role of Rho in G protein-coupled receptor signal transduction. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 459–489.

    Article  CAS  PubMed  Google Scholar 

  52. Sakurada S, Okamoto H, Takuwa N, Sugimoto N, and Takuwa Y. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am. J. Physiol. Cell. Physiol. 2001; 281: C571–C578.

    CAS  PubMed  Google Scholar 

  53. Sato K, Rodman DM, and McMurtry IF. Hypoxia inhibits increased ET8 receptor-mediated NO synthesis in hypertensive rat lungs. Am. J. Physiol. 1999; 276: L571–L581.

    CAS  PubMed  Google Scholar 

  54. Schoenwaelder SM and Burridge K. Bidirectional signaling between the cytoskeleton and integrins. Curr. Opin. Cell Biol. 1999; 11: 274–286.

    Article  CAS  PubMed  Google Scholar 

  55. Seasholtz TM, Zhang T, Morissette MR, Howes AL, Yang AH, and Brown JH. Increased expression and activity of RhoA are associated with increased DNA synthesis and reduced p27(Kip1) expression in the vasculature of hypertensive rats. Circ. Res. 2001; 89: 488–495.

    CAS  PubMed  Google Scholar 

  56. Shibata R, Kai H, Seki Y, Kato S, Morimatsu M, Kaibuchi K, and Imaizumi T. Role of Rhoassociated kinase in neointima formation after vascular injury. Circulation. 2001; 103: 284–289.

    CAS  PubMed  Google Scholar 

  57. Shimoda LA, Sham JSK, Shimoda TH, and Sylvester JT. L-type Ca+ channels, resting [Ca2+]i, and ET-1-induced responses in chronically hypoxic pulmonary myocytes. Am. J. Physiol. Lung Cell. Mol. Physiol. 2000; 279: L884–L894.

    CAS  PubMed  Google Scholar 

  58. Shimokawa H. Rho-kinase as a novel therapeutic target in treatment of cardiovascular diseases. J. Cardiovasc. Pharmacol. 2002; 39: 319–327.

    Article  CAS  PubMed  Google Scholar 

  59. Shimokawa H, Seto M, Katsumata N, Amano M, Kozai T, Yamawaki T, Kuwata K, Kandabashi T, Egashira K, Ikegaki I, Asano T, Kaibuchi K, and Takeshita A. Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res. 1999; 43: 1029–1039.

    Article  CAS  PubMed  Google Scholar 

  60. Slice LW, Han SK, and Simon MI. Galphaq signaling is required for Rho-dependent transcriptional activation of the cyclooxygenase-2 promoter in fibroblasts. J. Cell. Physiol. 2003; 194: 127–138.

    Article  CAS  PubMed  Google Scholar 

  61. Somlyo AP and Somlyo AV. Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J. Physiol. 2000; 522: 177–185.

    Article  CAS  PubMed  Google Scholar 

  62. Stark WW Jr., Blaskovich MA, Johnson BA, Qian Y, Vasudevan A, Pitt B, Hamilton AD, Sebti SM, and Davies P. Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells. Am. J. Physiol. 1998; 275: L55–L63.

    CAS  PubMed  Google Scholar 

  63. Takemoto M, Sun J, Hiroki J, Shimokawa H, and Liao JK. Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002; 106: 57–62.

    Article  CAS  PubMed  Google Scholar 

  64. Tsuji T, Ishizaki T, Okamoto M, Higashida C, Kimura K, Furuyashiki T, Arakawa Y, Birge RB, Nakamoto T, Hirai H, and Narumiya S. ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts. J. Cell. Biol. 2002; 157: 819–830.

    Article  CAS  PubMed  Google Scholar 

  65. Tuder RM and Zaiman AL. Prostacyclin analogs as the brakes for pulmonary artery smooth muscle cell proliferation: is it sufficient to treat severe pulmonary hypertension? Am. J. Respir. Cell. Mol. Biol. 2002; 26: 171–174.

    CAS  PubMed  Google Scholar 

  66. Wang Z, Jin N, Ganguli S, Swartz DR, Li L, and Rhoades RA. Rho-kinase activation is involved in hypoxia-induced pulmonary vasoconstriction. Am. J. Respir. Cell. Mol. Biol. 2001; 25: 628–635.

    CAS  PubMed  Google Scholar 

  67. Welsh CF, Roovers K, Villanueva J, Liu Y, Schwartz MA, and Assoian RK. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nat. Cell. Biol. 2001; 3: 950–957.

    Article  CAS  PubMed  Google Scholar 

  68. Yamakawa T, Tanaka S-i, Numaguchi K, Yamakawa Y, Motley ED, Ichihara S, and Inagami T. Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells. Hypertension. 2000; 35: 313–318.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Colorado Health Sciences Center, Denver, Colorado

    Ivan F. McMurtry, Natalie R. Bauer, Sarah A. Gebb, Karen A. Fagan, Tetsutaro Nagaoka, Masahiko Oka & Tom P. Robertson

  2. University of Georgia, Athens, Georgia, USA

    Ivan F. McMurtry, Natalie R. Bauer, Sarah A. Gebb, Karen A. Fagan, Tetsutaro Nagaoka, Masahiko Oka & Tom P. Robertson

Authors
  1. Ivan F. McMurtry
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natalie R. Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah A. Gebb
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karen A. Fagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsutaro Nagaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masahiko Oka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tom P. Robertson
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Medicine, University of California, San Diego School of Medicine, San Diego, California

    Jason X. -J. Yuan M.D., Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2004 Kluwer Academic Publishers

About this chapter

Cite this chapter

McMurtry, I.F. et al. (2004). Rho/Rho-kinase Signaling in Hypoxic Pulmonary Hypertension. In: Yuan, J.X.J. (eds) Hypoxic Pulmonary Vasoconstriction. Developments in Cardiovascular Medicine, vol 252. Springer, Boston, MA. https://doi.org/10.1007/1-4020-7858-7_24

Download citation

  • DOI: https://doi.org/10.1007/1-4020-7858-7_24

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4020-7857-6

  • Online ISBN: 978-1-4020-7858-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation