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Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, Komada Y, Mitani Y - PLoS ONE (2015)

Bottom Line: Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages.Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals.We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

ABSTRACT
We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

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Summary: Phenotypically modulated SMCs and inflammation in the progression of obstructive pulmonary vasculopathy.Abbreviations are described in Figs. 1, 2, and 8.
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pone.0118655.g010: Summary: Phenotypically modulated SMCs and inflammation in the progression of obstructive pulmonary vasculopathy.Abbreviations are described in Figs. 1, 2, and 8.

Mentions: Amid controversy in the cell type responsible for progressive obstructive pulmonary vasculopathy in human PAH, [1–4] we obtained consistent pathological findings in specific lesions in this model which mimicked previous immunohistochemical findings reported by Yi and Atkinson, [1,2] and electron microscopic findings in human PAH. [3,27,28] We demonstrated that immature and mature SMCs and inflammatory cells, which were previously poorly appreciated in a Sugen/hypoxia rat model, were temporally and topologically associated with the progression of an occlusive pulmonary vasculopathy. We further demonstrated that PAH-related inflammatory genes were progressively or persistently up-regulated and differentially expressed in this progressive model, compared with in the non-progressive model induced by exposure to chronic hypoxia alone. These findings are based on expression pattern of multiple SMC markers, pathological characteristics and gene expression profile in this progressive model. The progression of various pathological parameters and the positive correlation between the percentage of occlusive lesions and RVSP was quantitatively demonstrated in the present study, which is in line with the previous studies of the SuHx model and human PAH [16,29,30]. An early increase (at 3–8 weeks) in RVSP and the RV/LV+S ratio in spite of the later peak (at 13 weeks) in the indices of occlusive vasculopathy could be related to the vasoconstrictive nature of vessels in the early stage of disease (at 3–5 weeks) and the later decrease in cardiac output, which is associated with advanced pulmonary vasculopathy, as in previous studies [29,31], suggesting uncertainty in the causality between an increase in RVSP and the development of occlusive vasculopathy. The present findings are summarized in a schematic diagram (Fig. 10).


Potential contribution of phenotypically modulated smooth muscle cells and related inflammation in the development of experimental obstructive pulmonary vasculopathy in rats.

Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, Komada Y, Mitani Y - PLoS ONE (2015)

Summary: Phenotypically modulated SMCs and inflammation in the progression of obstructive pulmonary vasculopathy.Abbreviations are described in Figs. 1, 2, and 8.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4340876&req=5

pone.0118655.g010: Summary: Phenotypically modulated SMCs and inflammation in the progression of obstructive pulmonary vasculopathy.Abbreviations are described in Figs. 1, 2, and 8.
Mentions: Amid controversy in the cell type responsible for progressive obstructive pulmonary vasculopathy in human PAH, [1–4] we obtained consistent pathological findings in specific lesions in this model which mimicked previous immunohistochemical findings reported by Yi and Atkinson, [1,2] and electron microscopic findings in human PAH. [3,27,28] We demonstrated that immature and mature SMCs and inflammatory cells, which were previously poorly appreciated in a Sugen/hypoxia rat model, were temporally and topologically associated with the progression of an occlusive pulmonary vasculopathy. We further demonstrated that PAH-related inflammatory genes were progressively or persistently up-regulated and differentially expressed in this progressive model, compared with in the non-progressive model induced by exposure to chronic hypoxia alone. These findings are based on expression pattern of multiple SMC markers, pathological characteristics and gene expression profile in this progressive model. The progression of various pathological parameters and the positive correlation between the percentage of occlusive lesions and RVSP was quantitatively demonstrated in the present study, which is in line with the previous studies of the SuHx model and human PAH [16,29,30]. An early increase (at 3–8 weeks) in RVSP and the RV/LV+S ratio in spite of the later peak (at 13 weeks) in the indices of occlusive vasculopathy could be related to the vasoconstrictive nature of vessels in the early stage of disease (at 3–5 weeks) and the later decrease in cardiac output, which is associated with advanced pulmonary vasculopathy, as in previous studies [29,31], suggesting uncertainty in the causality between an increase in RVSP and the development of occlusive vasculopathy. The present findings are summarized in a schematic diagram (Fig. 10).

Bottom Line: Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages.Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals.We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.

ABSTRACT
We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

Show MeSH
Related in: MedlinePlus