Understanding the Pathobiology of Pulmonary Vascular Disease

  • Kristin B. Highland


Pulmonary arterial hypertension (PAH) is a panvasculopathy that results in a progressive increase in pulmonary arterial pressure in association with variable degrees of pulmonary vascular remodeling, vasoconstriction, and in situ thrombosis. This leads to concentric obliteration of the pulmonary arteriole and the development of plexiform lesions that in turn result in an increased pulmonary vascular resistance and eventual right heart failure and death. The complex pathological features of pulmonary arterial hypertension (PAH) are highlighted in this review. A greater understanding of this complex pathobiology of PAH is essential for the future development of new therapeutic options.


Pulmonary Hypertension Pulmonary Arterial Hypertension Right Ventricle Vasoactive Intestinal Peptide Pulmonary Vascular Resistance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Figure 13.1 courtesy of Ellen Reimer, M.D., J.D., Assistant Professor of Pathology and Laboratory Medicine, Medical University of South Carolina.

Figures 13.2 and 13.3 courtesy of Russel Harley, M.D., Professor of Pathology and Laboratory Medicine, MUS and Chairman, Dept. of Pulmonary and Mediastinal Pathology, AFIP.

DisclosuresDr. Highland is on the speaker’s bureau and/or has grants/contracts with Actelion Pharmaceuticals, Gilead Sciences, and Pfizer Inc.


  1. 1.
    Heath D. Longitudinal muscle in pulmonary arteries. J Pathol Bacteriol. 1963;85:407–12.CrossRefGoogle Scholar
  2. 2.
    Kovacs G, Berghold A, Scheidl S, Olschewski H. Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review. Eur Respir J. 2009;34:888–94.PubMedCrossRefGoogle Scholar
  3. 3.
    Badesch DB, Championm HC, Sanchez MA, Hoeper MM, Loyd JE, Manes A, et al. Diagnosis and assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009;54(Suppl):S55–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Behr J, Ryu JH. Pulmonary hypertension in interstitial lung disease. Eur Respir J. 2009;34:888–94.CrossRefGoogle Scholar
  5. 5.
    Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;31:1357–67.CrossRefGoogle Scholar
  6. 6.
    Oswald-Mammosser M, Weitzenblum E, Quoix E, et al. Prognostic factors in COPD patients receiving long-term oxygen therapy. Importance of pulmonary artery pressure. Chest. 1995;107:1193–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Hamada K, Nagai S, Tanaka S, et al. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest. 2007;131:650–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Hoeper MM. The new definition of pulmonary hypertension. Eur Respir J. 2009;34:790–1.PubMedCrossRefGoogle Scholar
  9. 9.
    Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med. 2009;30:376–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Tuder RM, Chacon M, Alger LA, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J Pathol. 2001;195:367–74.PubMedCrossRefGoogle Scholar
  11. 11.
    Tuder RM, Groves BM, Badesch DB, Voelkel NF. Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension. Am J Pathol. 1994;144:275–85.PubMedGoogle Scholar
  12. 12.
    Archer SL, Weir K, Wilkins MR. Basic science of pulmonary arterial hypertension for clinicians. New concepts and experimental therapies. Circulation. 2010;121:2045–66.PubMedCrossRefGoogle Scholar
  13. 13.
    Bronicki RA, Baden HP. Pathophysiology of right ventricular failure in pulmonary hypertension. Pediatr Crit Care Med. 2010;11(Suppl):S15–22.PubMedCrossRefGoogle Scholar
  14. 14.
    McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006;114:1417–31.PubMedCrossRefGoogle Scholar
  15. 15.
    Nagendran J, Archer SL, Soliman D, et al. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility. Circulation. 2007;116:238–48.PubMedCrossRefGoogle Scholar
  16. 16.
    Sharma S, Taegtmeyer H, Adrogue J, et al. Dynamic changes of gene expression in hypoxia-induced right ventricular hypertrophy. Am J Physiol Heart Circ Physiol. 2004;286:H1185–92.PubMedCrossRefGoogle Scholar
  17. 17.
    Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(Suppl):S43–54.PubMedCrossRefGoogle Scholar
  18. 18.
    McLaughlin VV, Presberg KW, Doyle RL, et al. Prognosis of pulmonary arterial hypertension: ACCP evidence based clinical practice guidelines. Chest. 2004;126(1 Suppl):78S–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Yuan JXJ, Rubin LJ. Pathogenesis of pulmonary arterial hypertension: the need for multiple hits. Circulation. 2005;111:534–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Cogan JD, Pauciulo MW, Batchman AP, et al. High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:590–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet. 2000;67:737–44.PubMedCrossRefGoogle Scholar
  22. 22.
    Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004;43:33S–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Trembath R, Thomson J, Machado R, et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med. 2001;345:325–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Eddahibi S, Chaouat A, Morrell N, et al. Polymoprphism of the serotonin transporter gene and pulmonary hypertension in chronic obstructive pulmonary disease. Circulation. 2003;108:1839–44.PubMedCrossRefGoogle Scholar
  25. 25.
    Remillard CV, Tigno DD, Platoshyn O, et al. Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension. Am J Physiol Cell Physiol. 2007;292:C1837–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Yu Y, Keller SH, Remillard CV, et al. A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation. 2009;119:2313–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Christman BW, McPherson CD, Newman JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med. 1992;327:70–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Tuder RM, Cool CD, Geraci MW, et al. Pulmonary prostacyclin synthase is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:1925–32.PubMedGoogle Scholar
  29. 29.
    Stewart DJ, Levy RD, Cernacek P, Langleben D. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med. 1991;114:464–9.PubMedGoogle Scholar
  30. 30.
    Rubens C, Ewert R, Halank M, et al. Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest. 2001;120:1562–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Giaid A, Yanagisawa M, Langleben D, et al. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993;328:1732–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Cella G, Bellotto F, Tona F, et al. Plasma markers of endothelial dysfunction in pulmonary hypertension. Chest. 2001;120:1226–30.PubMedCrossRefGoogle Scholar
  33. 33.
    Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995;333:214–21.PubMedCrossRefGoogle Scholar
  34. 34.
    Eddahibi S, Humbert M, Fadel E, et al. Serotonin transporter overexpression is responsible for pulmonary artery smooth muscle hyperplasia in primary pulmonary hypertension. J Clin Invest. 2001;108:1141–50.PubMedGoogle Scholar
  35. 35.
    Morecroft I, Heeley RP, Prentice HM, et al. 5-Hdroxytryptoamine receptors mediating contraction in human small pulmonary arteries: importance of the 5-HT1b receptor. Br J Pharmacol. 1999;128:730–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Petkov V, Mosgoeller W, Ziesche R, et al. Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. J Clin Invest. 2003;111:1339–46.PubMedGoogle Scholar
  37. 37.
    Lesprit P, Godeau B, Authier FJ, et al. Pulmonary hypertension in POEMS syndrome: a new feature mediated by cytokines. Am J Respir Crit Care Med. 1998;157:907–11.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2012

Authors and Affiliations

  1. 1.Pulmonary Hypertension ProgramMedical University of South CarolinaCharlestonUSA

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