Site-specific responses to monocrotaline-induced vascular injury: evidence for two distinct mechanisms of remodeling.

Monocrotaline (MCT)-induced pulmonary vascular injury was used to begin studying the mechanism(s) of vascular remodeling in Fischer 344 rats, using extracellular matrix (ECM) gene expression to define areas of remodeling. By day 28 after injection, pulmonary artery pressures were increased and right ventricular hypertrophy had developed compared with normal controls. Tropoelastin, fibronectin, and alpha 1(I) procollagen mRNA levels increased at least 2-fold by day 28. In situ hybridization demonstrated tropoelastin gene expression by cells adjacent to the lumen and procollagen gene expression at the medial-adventitial border in both small muscular and large elastic pulmonary arteries. This pattern of gene expression was observed as early as 1 wk after MCT injury. These observations indicated two distinct areas of remodeling, one along the vascular lumen at the site of monocrotaline-induced injury and the other at a second distinct site. To determine whether other differences may be involved at these two sites, the presence of transforming growth factor-beta (TGF-beta) was studied. Total TGF-beta protein was 4-fold higher in remodeling lungs compared with normal lungs. Gene expression for all three isoforms of TGF-beta colocalized with tropoelastin gene expression along the vascular lumen but not with alpha 1(I) procollagen gene expression. These results suggest a complex site-specific response to injury mediated by two distinct pathways in this model of pulmonary vascular remodeling.

[1]  D. Schuster,et al.  The role of vascular injury and hemodynamics in rat pulmonary artery remodeling. , 1996, The Journal of clinical investigation.

[2]  L. Gold,et al.  Active Macrophage-Associated TGF-f3 Co-Localizes with Type I Procollagen Gene Expression in Atherosclerotic Human Pulmonary Arteries , 2007 .

[3]  R. Mecham,et al.  Persistence, re-expression, and induction of pulmonary arterial fibronectin, tropoelastin, and type I procollagen mRNA expression in neonatal hypoxic pulmonary hypertension. , 1994, The American journal of pathology.

[4]  D. Miller,et al.  Expression of transforming growth factor-beta mRNAs and proteins in pulmonary vascular remodeling in the sheep air embolization model of pulmonary hypertension. , 1994, American journal of respiratory cell and molecular biology.

[5]  M. Ferguson,et al.  Smooth muscle cell expression of extracellular matrix genes after arterial injury. , 1994, The American journal of pathology.

[6]  G. Gibbons,et al.  The emerging concept of vascular remodeling. , 1994, The New England journal of medicine.

[7]  L. Gold,et al.  Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta. , 1994, American Journal of Pathology.

[8]  R. Ross,et al.  Rous-Whipple Award Lecture. Atherosclerosis: a defense mechanism gone awry. , 1993, The American journal of pathology.

[9]  M. Gillespie,et al.  Temporal alterations in specific basement membrane components in lungs from monocrotaline-treated rats. , 1993, American journal of respiratory cell and molecular biology.

[10]  R. Mecham,et al.  Active collagen synthesis by pulmonary arteries in human primary pulmonary hypertension. , 1993, The American journal of pathology.

[11]  J. Isner,et al.  Expression of transforming growth factor-beta 1 is increased in human vascular restenosis lesions. , 1992, The Journal of clinical investigation.

[12]  S. Schwartz,et al.  Rat carotid neointimal smooth muscle cells reexpress a developmentally regulated mRNA phenotype during repair of arterial injury. , 1992, Circulation research.

[13]  R. Mecham,et al.  Transforming growth factor-beta 1 is decreased in remodeling hypertensive bovine pulmonary arteries. , 1992, The Journal of clinical investigation.

[14]  R. Mecham,et al.  Extracellular matrix protein gene expression in atherosclerotic hypertensive pulmonary arteries. , 1992, The American journal of pathology.

[15]  B. Meyrick,et al.  Sequence of structural changes and elastin peptide release during vascular remodelling in sheep with chronic pulmonary hypertension induced by air embolization. , 1991, The American journal of pathology.

[16]  S. Schwartz,et al.  Production of transforming growth factor beta 1 during repair of arterial injury. , 1991, The Journal of clinical investigation.

[17]  J. Reindel,et al.  The effects of monocrotaline pyrrole on cultured bovine pulmonary artery endothelial and smooth muscle cells. , 1991, The American journal of pathology.

[18]  H. Moses,et al.  Transforming growth factor-beta activity in sheep lung lymph during the development of pulmonary hypertension. , 1990, The Journal of clinical investigation.

[19]  S. Yohn,et al.  An antifibrotic agent reduces blood pressure in established pulmonary hypertension in the rat. , 1990, Journal of applied physiology.

[20]  R. Pierce,et al.  Collagen and elastin metabolism in hypertensive pulmonary arteries of rats. , 1990, Circulation research.

[21]  R. Mecham,et al.  Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. , 1989, The American journal of pathology.

[22]  B. Groves,et al.  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. , 1989, Circulation.

[23]  M. Sporn,et al.  Macrophage production of transforming growth factor beta and fibroblast collagen synthesis in chronic pulmonary inflammation , 1989, The Journal of experimental medicine.

[24]  D. Wilson,et al.  Progressive inflammatory and structural changes in the pulmonary vasculature of monocrotaline-treated rats. , 1989, Microvascular research.

[25]  F. Keeley,et al.  Altered elastin and collagen synthesis associated with progressive pulmonary hypertension induced by monocrotaline. A biochemical and ultrastructural study. , 1988, Laboratory investigation; a journal of technical methods and pathology.

[26]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[27]  N. Voelkel,et al.  Severe pulmonary hypertension and arterial adventitial changes in newborn calves at 4,300 m. , 1987, Journal of applied physiology.

[28]  C. Ruppert,et al.  Reduction of chronic hypoxic pulmonary hypertension in the rat by an inhibitor of collagen production. , 1987, The American review of respiratory disease.

[29]  W. Edwards,et al.  Primary pulmonary hypertension: a histopathologic study of 80 cases. , 1985, Mayo Clinic proceedings.

[30]  R. Trelstad,et al.  Reduction of chronic hypoxic pulmonary hypertension in the rat by beta-aminopropionitrile. , 1984, Journal of applied physiology: respiratory, environmental and exercise physiology.

[31]  F. Ghodsi,et al.  Changes in pulmonary structure and function induced by monocrotaline intoxication. , 1981, The American journal of physiology.

[32]  L. Reid,et al.  Development of Crotalaria pulmonary hypertension: hemodynamic and structural study. , 1980, The American journal of physiology.

[33]  C. Wagenvoort,et al.  Pathology of pulmonary hypertension , 1977 .

[34]  J. LeónCastro,et al.  [Primary pulmonary hypertension]. , 1971, Revista clinica espanola.

[35]  E. Wood,et al.  The structure of the pulmonary trunk at different ages and in cases of pulmonary hypertension and pulmonary stenosis. , 1959, The Journal of pathology and bacteriology.