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. 1996 Jul 15;98(2):434–442. doi: 10.1172/JCI118809

The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

Y Tanaka 1, D P Schuster 1, E C Davis 1, G A Patterson 1, M D Botney 1
PMCID: PMC507447  PMID: 8755654

Abstract

Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury. Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A non-neointimal pattern of remodeling after mild monocrotaline-induced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-beta gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.

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Selected References

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  1. Bahadori L., Milder J., Gold L., Botney M. Active macrophage-associated TGF-beta co-localizes with type I procollagen gene expression in atherosclerotic human pulmonary arteries. Am J Pathol. 1995 May;146(5):1140–1149. [PMC free article] [PubMed] [Google Scholar]
  2. Botney M. D., Bahadori L., Gold L. I. Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. Am J Pathol. 1994 Feb;144(2):286–295. [PMC free article] [PubMed] [Google Scholar]
  3. Botney M. D., Kaiser L. R., Cooper J. D., Mecham R. P., Parghi D., Roby J., Parks W. C. Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries. Am J Pathol. 1992 Feb;140(2):357–364. [PMC free article] [PubMed] [Google Scholar]
  4. Botney M. D., Liptay M. J., Kaiser L. R., Cooper J. D., Parks W. C., Mecham R. P. Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension. Am J Pathol. 1993 Jul;143(1):121–129. [PMC free article] [PubMed] [Google Scholar]
  5. Botney M. D., Parks W. C., Crouch E. C., Stenmark K., Mecham R. P. Transforming growth factor-beta 1 is decreased in remodeling hypertensive bovine pulmonary arteries. J Clin Invest. 1992 May;89(5):1629–1635. doi: 10.1172/JCI115759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bruner L. H., Carpenter L. J., Hamlow P., Roth R. A. Effect of a mixed function oxidase inducer and inhibitor on monocrotaline pyrrole pneumotoxicity. Toxicol Appl Pharmacol. 1986 Sep 30;85(3):416–427. doi: 10.1016/0041-008x(86)90349-2. [DOI] [PubMed] [Google Scholar]
  7. Clowes A. W., Reidy M. A., Clowes M. M. Mechanisms of stenosis after arterial injury. Lab Invest. 1983 Aug;49(2):208–215. [PubMed] [Google Scholar]
  8. Davis E. C. Smooth muscle cell to elastic lamina connections in developing mouse aorta. Role in aortic medial organization. Lab Invest. 1993 Jan;68(1):89–99. [PubMed] [Google Scholar]
  9. Fingerle J., Au Y. P., Clowes A. W., Reidy M. A. Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. Arteriosclerosis. 1990 Nov-Dec;10(6):1082–1087. doi: 10.1161/01.atv.10.6.1082. [DOI] [PubMed] [Google Scholar]
  10. Giaid A., Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med. 1995 Jul 27;333(4):214–221. doi: 10.1056/NEJM199507273330403. [DOI] [PubMed] [Google Scholar]
  11. Giaid A., Yanagisawa M., Langleben D., Michel R. P., Levy R., Shennib H., Kimura S., Masaki T., Duguid W. P., Stewart D. J. Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med. 1993 Jun 17;328(24):1732–1739. doi: 10.1056/NEJM199306173282402. [DOI] [PubMed] [Google Scholar]
  12. Gibbons G. H., Dzau V. J. The emerging concept of vascular remodeling. N Engl J Med. 1994 May 19;330(20):1431–1438. doi: 10.1056/NEJM199405193302008. [DOI] [PubMed] [Google Scholar]
  13. Glagov S., Ozoa A. K. Significance of the relatively low incidence of atherosclerosis in the pulmonary, renal, and mesenteric arteries. Ann N Y Acad Sci. 1968 Nov 21;149(2):940–955. doi: 10.1111/j.1749-6632.1968.tb53848.x. [DOI] [PubMed] [Google Scholar]
  14. HEATH D., WOOD E. H., DUSHANE J. W., EDWARDS J. E. The relation of age and blood pressure to atheroma in the pulmonary arteries and thoracic aorta in congenital heart disease. Lab Invest. 1960 Mar-Apr;9:259–272. [PubMed] [Google Scholar]
  15. HEATH D., WOOD E. H., DUSHANE J. W., EDWARDS J. E. The structure of the pulmonary trunk at different ages and in cases of pulmonary hypertension and pulmonary stenosis. J Pathol Bacteriol. 1959 Apr;77(2):443–456. doi: 10.1002/path.1700770216. [DOI] [PubMed] [Google Scholar]
  16. Jones R., Zapol W. M., Reid L. Oxygen toxicity and restructuring of pulmonary arteries--a morphometric study. The response to 4 weeks' exposure to hyperoxia and return to breathing air. Am J Pathol. 1985 Nov;121(2):212–223. [PMC free article] [PubMed] [Google Scholar]
  17. Kameji R., Otsuka H., Hayashi Y. Increase of collagen synthesis in pulmonary arteries of monocrotaline-treated rats. Experientia. 1980 Apr 15;36(4):441–442. doi: 10.1007/BF01975136. [DOI] [PubMed] [Google Scholar]
  18. Kolpakov V., Rekhter M. D., Gordon D., Wang W. H., Kulik T. J. Effect of mechanical forces on growth and matrix protein synthesis in the in vitro pulmonary artery. Analysis of the role of individual cell types. Circ Res. 1995 Oct;77(4):823–831. doi: 10.1161/01.res.77.4.823. [DOI] [PubMed] [Google Scholar]
  19. Leung D. Y., Glagov S., Mathews M. B. A new in vitro system for studying cell response to mechanical stimulation. Different effects of cyclic stretching and agitation on smooth muscle cell biosynthesis. Exp Cell Res. 1977 Oct 15;109(2):285–298. doi: 10.1016/0014-4827(77)90008-8. [DOI] [PubMed] [Google Scholar]
  20. Lipke D. W., Arcot S. S., Gillespie M. N., Olson J. W. Temporal alterations in specific basement membrane components in lungs from monocrotaline-treated rats. Am J Respir Cell Mol Biol. 1993 Oct;9(4):418–428. doi: 10.1165/ajrcmb/9.4.418. [DOI] [PubMed] [Google Scholar]
  21. Liptay M. J., Parks W. C., Mecham R. P., Roby J., Kaiser L. R., Cooper J. D., Botney M. D. Neointimal macrophages colocalize with extracellular matrix gene expression in human atherosclerotic pulmonary arteries. J Clin Invest. 1993 Feb;91(2):588–594. doi: 10.1172/JCI116238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Mizuta T., Kawaguchi A., Nakahara K., Kawashima Y. Simplified rat lung transplantation using a cuff technique. J Thorac Cardiovasc Surg. 1989 Apr;97(4):578–581. [PubMed] [Google Scholar]
  23. Nikkari S. T., Järveläinen H. T., Wight T. N., Ferguson M., Clowes A. W. Smooth muscle cell expression of extracellular matrix genes after arterial injury. Am J Pathol. 1994 Jun;144(6):1348–1356. [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Pietra G. G., Edwards W. D., Kay J. M., Rich S., Kernis J., Schloo B., Ayres S. M., Bergofsky E. H., Brundage B. H., Detre K. M. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation. 1989 Nov;80(5):1198–1206. doi: 10.1161/01.cir.80.5.1198. [DOI] [PubMed] [Google Scholar]
  26. Poiani G. J., Tozzi C. A., Yohn S. E., Pierce R. A., Belsky S. A., Berg R. A., Yu S. Y., Deak S. B., Riley D. J. Collagen and elastin metabolism in hypertensive pulmonary arteries of rats. Circ Res. 1990 Apr;66(4):968–978. doi: 10.1161/01.res.66.4.968. [DOI] [PubMed] [Google Scholar]
  27. Prosser I. W., Stenmark K. R., Suthar M., Crouch E. C., Mecham R. P., Parks W. C. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol. 1989 Dec;135(6):1073–1088. [PMC free article] [PubMed] [Google Scholar]
  28. Rosenberg H. C., Rabinovitch M. Endothelial injury and vascular reactivity in monocrotaline pulmonary hypertension. Am J Physiol. 1988 Dec;255(6 Pt 2):H1484–H1491. doi: 10.1152/ajpheart.1988.255.6.H1484. [DOI] [PubMed] [Google Scholar]
  29. Ross R. Rous-Whipple Award Lecture. Atherosclerosis: a defense mechanism gone awry. Am J Pathol. 1993 Oct;143(4):987–1002. [PMC free article] [PubMed] [Google Scholar]
  30. SCHOENTAL R., HEAD M. A. Pathological changes in rats as a result of treatment with monocrotaline. Br J Cancer. 1955 Mar;9(1):229–237. doi: 10.1038/bjc.1955.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Stenmark K. R., Fasules J., Hyde D. M., Voelkel N. F., Henson J., Tucker A., Wilson H., Reeves J. T. Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m. J Appl Physiol (1985) 1987 Feb;62(2):821–830. doi: 10.1152/jappl.1987.62.2.821. [DOI] [PubMed] [Google Scholar]
  32. Stenmark K. R., Morganroth M. L., Remigio L. K., Voelkel N. F., Murphy R. C., Henson P. M., Mathias M. M., Reeves J. T. Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension. Am J Physiol. 1985 Jun;248(6 Pt 2):H859–H866. doi: 10.1152/ajpheart.1985.248.6.H859. [DOI] [PubMed] [Google Scholar]
  33. Todorovich-Hunter L., Dodo H., Ye C., McCready L., Keeley F. W., Rabinovitch M. Increased pulmonary artery elastolytic activity in adult rats with monocrotaline-induced progressive hypertensive pulmonary vascular disease compared with infant rats with nonprogressive disease. Am Rev Respir Dis. 1992 Jul;146(1):213–223. doi: 10.1164/ajrccm/146.1.213. [DOI] [PubMed] [Google Scholar]
  34. Todorovich-Hunter L., Johnson D. J., Ranger P., Keeley F. W., Rabinovitch M. Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline. A biochemical and ultrastructural study. Lab Invest. 1988 Feb;58(2):184–195. [PubMed] [Google Scholar]
  35. Tozzi C. A., Poiani G. J., Harangozo A. M., Boyd C. D., Riley D. J. Pressure-induced connective tissue synthesis in pulmonary artery segments is dependent on intact endothelium. J Clin Invest. 1989 Sep;84(3):1005–1012. doi: 10.1172/JCI114221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tuder R. M., Flook B. E., Voelkel N. F. Increased gene expression for VEGF and the VEGF receptors KDR/Flk and Flt in lungs exposed to acute or to chronic hypoxia. Modulation of gene expression by nitric oxide. J Clin Invest. 1995 Apr;95(4):1798–1807. doi: 10.1172/JCI117858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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]

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