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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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Immature smooth muscle cells in cellular intimal lesions.Photomicrographs of serial sections of cellular intimal lesions (Panels A, B). Cells staining positive for αSMA, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7 were regarded as representing phenotypically modulated immature smooth muscle cells. Arrows indicate immature smooth muscle cells. Other abbreviations are described in Figs. 2 and 3.
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pone.0118655.g004: Immature smooth muscle cells in cellular intimal lesions.Photomicrographs of serial sections of cellular intimal lesions (Panels A, B). Cells staining positive for αSMA, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7 were regarded as representing phenotypically modulated immature smooth muscle cells. Arrows indicate immature smooth muscle cells. Other abbreviations are described in Figs. 2 and 3.

Mentions: In intimal lesions, we observed 2 phenotypically distinct subtypes of SMCs: hyperchromatic and oval cells staining positive for αSMA, vimentin, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7, representing phenotypically modulated immature SMCs (Fig. 4) and cells staining positive for αSMA, SM1, SM2, HHF35 and CGA7 but weakly positive with vimentin, representing mature SMCs (Fig. 5). Cellular intimal lesions typically comprised immature SMCs, which included CD68-positive intimal macrophages and PCNA-positive cells and were positive for tenascin C (Fig. 4Bi-k). In contrast, intimal fibrosis with dense deposits of elastin comprised mature SMCs, in which few CD68-positive macrophages and PCNA-positive cells were observed (Fig. 5Bij). In the media of small pulmonary arteries, hyperchromatic and oval cells with mature SMC phenotype were occasionally observed (S2 Fig.). Quantitatively, immature SMC-dominant lesions accounted for 87.5% of lesions with cellular intimal thickening and 14.0% of lesions with intimal fibrosis (chi-square analysis, P<.0001) (Fig. 6).


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)

Immature smooth muscle cells in cellular intimal lesions.Photomicrographs of serial sections of cellular intimal lesions (Panels A, B). Cells staining positive for αSMA, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7 were regarded as representing phenotypically modulated immature smooth muscle cells. Arrows indicate immature smooth muscle cells. Other abbreviations are described in Figs. 2 and 3.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118655.g004: Immature smooth muscle cells in cellular intimal lesions.Photomicrographs of serial sections of cellular intimal lesions (Panels A, B). Cells staining positive for αSMA, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7 were regarded as representing phenotypically modulated immature smooth muscle cells. Arrows indicate immature smooth muscle cells. Other abbreviations are described in Figs. 2 and 3.
Mentions: In intimal lesions, we observed 2 phenotypically distinct subtypes of SMCs: hyperchromatic and oval cells staining positive for αSMA, vimentin, SM1 and HHF35 but weakly positive or negative with SM2 and CGA7, representing phenotypically modulated immature SMCs (Fig. 4) and cells staining positive for αSMA, SM1, SM2, HHF35 and CGA7 but weakly positive with vimentin, representing mature SMCs (Fig. 5). Cellular intimal lesions typically comprised immature SMCs, which included CD68-positive intimal macrophages and PCNA-positive cells and were positive for tenascin C (Fig. 4Bi-k). In contrast, intimal fibrosis with dense deposits of elastin comprised mature SMCs, in which few CD68-positive macrophages and PCNA-positive cells were observed (Fig. 5Bij). In the media of small pulmonary arteries, hyperchromatic and oval cells with mature SMC phenotype were occasionally observed (S2 Fig.). Quantitatively, immature SMC-dominant lesions accounted for 87.5% of lesions with cellular intimal thickening and 14.0% of lesions with intimal fibrosis (chi-square analysis, P<.0001) (Fig. 6).

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