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. 1994 Feb;144(2):275–285.

Exuberant endothelial cell growth and elements of inflammation are present in plexiform lesions of pulmonary hypertension.

R M Tuder 1, B Groves 1, D B Badesch 1, N F Voelkel 1
PMCID: PMC1887146  PMID: 7508683

Abstract

The plexiform lesion in primary pulmonary hypertension is a glomeruloid structure forming channels in branches of the pulmonary artery. These lesions have been considered an abnormal growth of modified smooth muscle cells. We present immunohistochemical evidence in 10 cases of plexogenic pulmonary hypertension that the plexiform channels and the concentric obliterative arteriopathy associated with these channels represent abnormal growth of factor VIII-related antigen-positive endothelial cells. In addition, these cells strongly expressed vimentin, a growth- and differentiation-related intermediate filament. Morphologically and immunohistochemically, the lesions resembled the neovascularization associated with the brain tumor glioblastoma multiform. Furthermore, we noted an exclusively perivascular inflammatory cell infiltrate (but no vasculitis) in seven of the 10 cases with plexogenic arteriopathy composed of T cells, B cells, and macrophages. Our findings indicate that the plexiform lesion may result from a deregulated growth of endothelial cells. The presence of perivascular inflammatory cells suggested that cytokines and growth factors may further influence the development of the plexiform lesion.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Balk A. G., Dingemans K. P., Wagenvoort C. A. The ultrastructure of the various forms of pulmonary arterial intimal fibrosis. Virchows Arch A Pathol Anat Histol. 1979 May 31;382(2):139–150. doi: 10.1007/BF01102870. [DOI] [PubMed] [Google Scholar]
  2. Berry G. J., Brunt E. M., Chamberlain D., Hruban R. H., Sibley R. K., Stewart S., Tazelaar H. D. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990 Nov-Dec;9(6):593–601. [PubMed] [Google Scholar]
  3. Bjornsson J., Edwards W. D. Primary pulmonary hypertension: a histopathologic study of 80 cases. Mayo Clin Proc. 1985 Jan;60(1):16–25. doi: 10.1016/s0025-6196(12)65277-x. [DOI] [PubMed] [Google Scholar]
  4. Blose S. H., Chacko S. Rings of intermediate (100 A) filament bundles in the perinuclear region of vascular endothelial cells. Their mobilization by colcemid and mitosis. J Cell Biol. 1976 Aug;70(2 Pt 1):459–466. doi: 10.1083/jcb.70.2.459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brock T. A., Dvorak H. F., Senger D. R. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol. 1991 Jan;138(1):213–221. [PMC free article] [PubMed] [Google Scholar]
  6. Burke A. P., Farb A., Virmani R. The pathology of primary pulmonary hypertension. Mod Pathol. 1991 Mar;4(2):269–282. [PubMed] [Google Scholar]
  7. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 37-1992. A 68-year-old woman with rheumatoid arthritis and pulmonary hypertension. N Engl J Med. 1992 Sep 17;327(12):873–880. doi: 10.1056/NEJM199209173271209. [DOI] [PubMed] [Google Scholar]
  8. Caslin A. W., Heath D., Madden B., Yacoub M., Gosney J. R., Smith P. The histopathology of 36 cases of plexogenic pulmonary arteriopathy. Histopathology. 1990 Jan;16(1):9–19. doi: 10.1111/j.1365-2559.1990.tb01054.x. [DOI] [PubMed] [Google Scholar]
  9. Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  11. Ferrari S., Battini R., Kaczmarek L., Rittling S., Calabretta B., de Riel J. K., Philiponis V., Wei J. F., Baserga R. Coding sequence and growth regulation of the human vimentin gene. Mol Cell Biol. 1986 Nov;6(11):3614–3620. doi: 10.1128/mcb.6.11.3614. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Folkman J. What is the role of endothelial cells in angiogenesis? Lab Invest. 1984 Dec;51(6):601–604. [PubMed] [Google Scholar]
  13. Gillespie M. N., Goldblum S. E., Cohen D. A., McClain C. J. Interleukin 1 bioactivity in the lungs of rats with monocrotaline-induced pulmonary hypertension. Proc Soc Exp Biol Med. 1988 Jan;187(1):26–32. doi: 10.3181/00379727-187-42632. [DOI] [PubMed] [Google Scholar]
  14. HEATH D., EDWARDS J. E. The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation. 1958 Oct;18(4 Pt 1):533–547. doi: 10.1161/01.cir.18.4.533. [DOI] [PubMed] [Google Scholar]
  15. Heath D., Smith P., Gosney J., Mulcahy D., Fox K., Yacoub M., Harris P. The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J. 1987 Sep;58(3):204–213. doi: 10.1136/hrt.58.3.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Herget J., Palecek F., Preclík P., Cermáková M., Vízek M., Petrovická M. Pulmonary hypertension induced by repeated pulmonary inflammation in the rat. J Appl Physiol Respir Environ Exerc Physiol. 1981 Sep;51(3):755–761. doi: 10.1152/jappl.1981.51.3.755. [DOI] [PubMed] [Google Scholar]
  17. Jakeman L. B., Winer J., Bennett G. L., Altar C. A., Ferrara N. Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues. J Clin Invest. 1992 Jan;89(1):244–253. doi: 10.1172/JCI115568. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jones D. K., Perry E. M., Grosso M. A., Voelkel N. F. Release of von Willebrand factor antigen (vWF:Ag) and eicosanoids during acute injury to the isolated rat lung. Am Rev Respir Dis. 1992 Jun;145(6):1410–1415. doi: 10.1164/ajrccm/145.6.1410. [DOI] [PubMed] [Google Scholar]
  19. Knighton D. R., Hunt T. K., Scheuenstuhl H., Halliday B. J., Werb Z., Banda M. J. Oxygen tension regulates the expression of angiogenesis factor by macrophages. Science. 1983 Sep 23;221(4617):1283–1285. doi: 10.1126/science.6612342. [DOI] [PubMed] [Google Scholar]
  20. McComb R. D., Bigner D. D. The biology of malignant gliomas--a comprehensive survey. Clin Neuropathol. 1984 May-Jun;3(3):93–106. [PubMed] [Google Scholar]
  21. McComb R. D., Jones T. R., Pizzo S. V., Bigner D. D. Immunohistochemical detection of factor VIII/von Willebrand factor in hyperplastic endothelial cells in glioblastoma multiforme and mixed glioma-sarcoma. J Neuropathol Exp Neurol. 1982 Sep;41(5):479–489. [PubMed] [Google Scholar]
  22. Meyrick B., Brigham K. L. Repeated Escherichia coli endotoxin-induced pulmonary inflammation causes chronic pulmonary hypertension in sheep. Structural and functional changes. Lab Invest. 1986 Aug;55(2):164–176. [PubMed] [Google Scholar]
  23. Meyrick B., Perkett E. A., Brigham K. L. Inflammation and models of chronic pulmonary hypertension. Am Rev Respir Dis. 1987 Sep;136(3):765–767. doi: 10.1164/ajrccm/136.3.765. [DOI] [PubMed] [Google Scholar]
  24. Meyrick B., Reid L. Development of pulmonary arterial changes in rats fed Crotalaria spectabilis. Am J Pathol. 1979 Jan;94(1):37–50. [PMC free article] [PubMed] [Google Scholar]
  25. Monacci W. T., Merrill M. J., Oldfield E. H. Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues. Am J Physiol. 1993 Apr;264(4 Pt 1):C995–1002. doi: 10.1152/ajpcell.1993.264.4.C995. [DOI] [PubMed] [Google Scholar]
  26. Montesano R. 1992 Mack Forster Award Lecture. Review. Regulation of angiogenesis in vitro. Eur J Clin Invest. 1992 Aug;22(8):504–515. doi: 10.1111/j.1365-2362.1992.tb01498.x. [DOI] [PubMed] [Google Scholar]
  27. NAEYE R. L., VENNART G. P. The structure and significance of pulmonary plexiform structures. Am J Pathol. 1960 May;36:593–605. [PMC free article] [PubMed] [Google Scholar]
  28. Palevsky H. I., Schloo B. L., Pietra G. G., Weber K. T., Janicki J. S., Rubin E., Fishman A. P. Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents. Circulation. 1989 Nov;80(5):1207–1221. doi: 10.1161/01.cir.80.5.1207. [DOI] [PubMed] [Google Scholar]
  29. Perkett E. A., Brigham K. L., Meyrick B. Granulocyte depletion attenuates sustained pulmonary hypertension and increased pulmonary vasoreactivity caused by continuous air embolization in sheep. Am Rev Respir Dis. 1990 Feb;141(2):456–465. doi: 10.1164/ajrccm/141.2.456. [DOI] [PubMed] [Google Scholar]
  30. Perkett E. A., Davidson J. M., Meyrick B. Sequence of structural changes and elastin peptide release during vascular remodelling in sheep with chronic pulmonary hypertension induced by air embolization. Am J Pathol. 1991 Dec;139(6):1319–1332. [PMC free article] [PubMed] [Google Scholar]
  31. Pietra G. G., Rüttner J. R. Specificity of pulmonary vascular lesions in primary pulmonary hypertension. A reappraisal. Respiration. 1987;52(2):81–85. doi: 10.1159/000195308. [DOI] [PubMed] [Google Scholar]
  32. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  33. Polverini P. J., Cotran P. S., Gimbrone M. A., Jr, Unanue E. R. Activated macrophages induce vascular proliferation. Nature. 1977 Oct 27;269(5631):804–806. doi: 10.1038/269804a0. [DOI] [PubMed] [Google Scholar]
  34. Rittling S. R., Coutinho L., Amram T., Kolbe M. AP-1/jun binding sites mediate serum inducibility of the human vimentin promoter. Nucleic Acids Res. 1989 Feb 25;17(4):1619–1633. doi: 10.1093/nar/17.4.1619. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  36. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  37. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  38. Smith P., Heath D. Electron microscopy of the plexiform lesion. Thorax. 1979 Apr;34(2):177–186. doi: 10.1136/thx.34.2.177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. TURNER P. P. SCHISTOSOMAL PULMONARY ARTERIAL HYPERTENSION IN EAST AFRICA. Br Heart J. 1964 Nov;26:821–831. doi: 10.1136/hrt.26.6.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Wagner D. D., Marder V. J. Biosynthesis of von Willebrand protein by human endothelial cells. Identification of a large precursor polypeptide chain. J Biol Chem. 1983 Feb 25;258(4):2065–2067. [PubMed] [Google Scholar]
  41. Wilson D. W., Segall H. J., Pan L. C., Dunston S. K. Progressive inflammatory and structural changes in the pulmonary vasculature of monocrotaline-treated rats. Microvasc Res. 1989 Jul;38(1):57–80. doi: 10.1016/0026-2862(89)90017-4. [DOI] [PubMed] [Google Scholar]
  42. Yamaki S., Wagenvoort C. A. Comparison of primary plexogenic arteriopathy in adults and children. A morphometric study in 40 patients. Br Heart J. 1985 Oct;54(4):428–434. doi: 10.1136/hrt.54.4.428. [DOI] [PMC free article] [PubMed] [Google Scholar]

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