Limits...
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.

Show MeSH

Related in: MedlinePlus

Progression of pulmonary hypertension and an occlusive pulmonary vasculopathy in Sugen/hypoxia rats.Effects of Sugen/hypoxia (SuHx) or hypoxia on body weight (A), right ventricular systolic pressure (RVSP) (B), the weight ratio of the right ventricle to the left ventricle + septum (RV/LV+S) (C), percentage of vessels accompanied by occlusive lesions among the small pulmonary arteries per lung section (D), and percentage of vessels accompanied by cellular intimal thickening or intimal fibrosis in all the small pulmonary arteries per lung section (E) during the experimental period. Body weight, RVSP, and R/VL+S ratio among 3 study groups at each time point (A, B, C) or these hemodynamic and morphological parameters at various time points (B, C, D, E) were compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. P<.05 vs. control; †P<.05 vs. hypoxia. F: Correlation between the percentage of occlusive lesions and RVSP (Pearson product-moment correlation coefficients). Values are mean ± SD.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4340876&req=5

pone.0118655.g001: Progression of pulmonary hypertension and an occlusive pulmonary vasculopathy in Sugen/hypoxia rats.Effects of Sugen/hypoxia (SuHx) or hypoxia on body weight (A), right ventricular systolic pressure (RVSP) (B), the weight ratio of the right ventricle to the left ventricle + septum (RV/LV+S) (C), percentage of vessels accompanied by occlusive lesions among the small pulmonary arteries per lung section (D), and percentage of vessels accompanied by cellular intimal thickening or intimal fibrosis in all the small pulmonary arteries per lung section (E) during the experimental period. Body weight, RVSP, and R/VL+S ratio among 3 study groups at each time point (A, B, C) or these hemodynamic and morphological parameters at various time points (B, C, D, E) were compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. P<.05 vs. control; †P<.05 vs. hypoxia. F: Correlation between the percentage of occlusive lesions and RVSP (Pearson product-moment correlation coefficients). Values are mean ± SD.

Mentions: All the experimental and control rats survived during the experimental period. Body weight in Sugen/hypoxia rats and in hypoxic rats was significantly lower than in control rats at during 1–5 weeks; body weight in SuHx rats was significantly lower than in hypoxic rats during 2–5 weeks (Fig. 1A, S2 Table). Mean systemic arterial pressure in Sugen/hypoxia and hypoxic rats was comparable to that in controls at the respective time point (data not shown).


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)

Progression of pulmonary hypertension and an occlusive pulmonary vasculopathy in Sugen/hypoxia rats.Effects of Sugen/hypoxia (SuHx) or hypoxia on body weight (A), right ventricular systolic pressure (RVSP) (B), the weight ratio of the right ventricle to the left ventricle + septum (RV/LV+S) (C), percentage of vessels accompanied by occlusive lesions among the small pulmonary arteries per lung section (D), and percentage of vessels accompanied by cellular intimal thickening or intimal fibrosis in all the small pulmonary arteries per lung section (E) during the experimental period. Body weight, RVSP, and R/VL+S ratio among 3 study groups at each time point (A, B, C) or these hemodynamic and morphological parameters at various time points (B, C, D, E) were compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. P<.05 vs. control; †P<.05 vs. hypoxia. F: Correlation between the percentage of occlusive lesions and RVSP (Pearson product-moment correlation coefficients). Values are mean ± SD.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118655.g001: Progression of pulmonary hypertension and an occlusive pulmonary vasculopathy in Sugen/hypoxia rats.Effects of Sugen/hypoxia (SuHx) or hypoxia on body weight (A), right ventricular systolic pressure (RVSP) (B), the weight ratio of the right ventricle to the left ventricle + septum (RV/LV+S) (C), percentage of vessels accompanied by occlusive lesions among the small pulmonary arteries per lung section (D), and percentage of vessels accompanied by cellular intimal thickening or intimal fibrosis in all the small pulmonary arteries per lung section (E) during the experimental period. Body weight, RVSP, and R/VL+S ratio among 3 study groups at each time point (A, B, C) or these hemodynamic and morphological parameters at various time points (B, C, D, E) were compared with a one-way analysis of variance followed by Tukey-Kramer multiple comparison test. P<.05 vs. control; †P<.05 vs. hypoxia. F: Correlation between the percentage of occlusive lesions and RVSP (Pearson product-moment correlation coefficients). Values are mean ± SD.
Mentions: All the experimental and control rats survived during the experimental period. Body weight in Sugen/hypoxia rats and in hypoxic rats was significantly lower than in control rats at during 1–5 weeks; body weight in SuHx rats was significantly lower than in hypoxic rats during 2–5 weeks (Fig. 1A, S2 Table). Mean systemic arterial pressure in Sugen/hypoxia and hypoxic rats was comparable to that in controls at the respective time point (data not shown).

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