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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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Cellular components in intimal and plexiform lesions.Photomicrographs (elastic van Gieson staining, EVG) of sprouting intimal lesion (Panels Aab) and sprouting plexiform lesion (Panel Ac) in rats 3 weeks after initial treatment. Serial sections of longitudinal views (Panels Ba-h) and cross sectional views (Panels Bi-l) of intimal lesions and serial sections of plexiform lesions (Panels Bm-p) in EVG, von Willebrand factor (VWF), α-smooth muscle actin staining (αSMA) and negative controls. Photomicrographs (confocal microscopy) of a section of the intimal and plexiform lesion (Panels C), by using antibodies for VWF and αSMA, were presented. TO-PRO-3, nuclear staining. Arrows indicate abnormal cells.
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pone.0118655.g002: Cellular components in intimal and plexiform lesions.Photomicrographs (elastic van Gieson staining, EVG) of sprouting intimal lesion (Panels Aab) and sprouting plexiform lesion (Panel Ac) in rats 3 weeks after initial treatment. Serial sections of longitudinal views (Panels Ba-h) and cross sectional views (Panels Bi-l) of intimal lesions and serial sections of plexiform lesions (Panels Bm-p) in EVG, von Willebrand factor (VWF), α-smooth muscle actin staining (αSMA) and negative controls. Photomicrographs (confocal microscopy) of a section of the intimal and plexiform lesion (Panels C), by using antibodies for VWF and αSMA, were presented. TO-PRO-3, nuclear staining. Arrows indicate abnormal cells.

Mentions: In the longitudinal and cross sections of intimal lesions, an intimal cell mass occluded the vessel lumen (Fig. 2Aab, Ba-l). VWF-positive endothelial cells formed a luminal monolayer, which covered the supporting ‘hyperchromatic and oval’ cells positive for αSMA in the intima-media complex (Fig. 2B, C). Sprouting intimal lesions, which were observed as early as 3 weeks, were associated with the fragmented internal and external elastic laminae. (Fig. 2Ab, Ba). The complex plexiform lesion, which was observed predominantly 13 weeks after initial treatment, comprised a plexus of aneurysmal and angiomatoid small vessels and supporting cellular and matrix compontents, was covered by remnants of elastic laminae. (Fig. 3A, S1A-B Fig.). The ‘sprouting’ plexiform lesion, which began to be observed even rarely as early as 3 weeks, was a focal projection originating from the parent vessel and frequently appeared to be located within an aneurismal dilatation of a side branch with fragmented elastic laminae (Fig. 2Ac, Bm, Fig. 3B, C, D). VWF-positive endothelial cells formed a monolayer on the luminal surface in the vascular channel-like structure, that was supported by αSMA+ supporting cells (Fig. 2Bm-p, C); in some complex plexiform lesions, endothelial monolayers covering vascular channel lumen were sparsely distributed and were separated by abundant αSMA+ supporting cell cluster and matrix deposition (Fig. 3A, S1C-D Fig.). αSMA+ dilatation lesions in plexiform lesions appeared to be contiguous with αSMA + media of the parent vessels, while αSMA+ supporting cells in plexiform lesions were continuous with αSMA+ supporting cells in the intima of some parent vessels (Fig. 3C, D).


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)

Cellular components in intimal and plexiform lesions.Photomicrographs (elastic van Gieson staining, EVG) of sprouting intimal lesion (Panels Aab) and sprouting plexiform lesion (Panel Ac) in rats 3 weeks after initial treatment. Serial sections of longitudinal views (Panels Ba-h) and cross sectional views (Panels Bi-l) of intimal lesions and serial sections of plexiform lesions (Panels Bm-p) in EVG, von Willebrand factor (VWF), α-smooth muscle actin staining (αSMA) and negative controls. Photomicrographs (confocal microscopy) of a section of the intimal and plexiform lesion (Panels C), by using antibodies for VWF and αSMA, were presented. TO-PRO-3, nuclear staining. Arrows indicate abnormal cells.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0118655.g002: Cellular components in intimal and plexiform lesions.Photomicrographs (elastic van Gieson staining, EVG) of sprouting intimal lesion (Panels Aab) and sprouting plexiform lesion (Panel Ac) in rats 3 weeks after initial treatment. Serial sections of longitudinal views (Panels Ba-h) and cross sectional views (Panels Bi-l) of intimal lesions and serial sections of plexiform lesions (Panels Bm-p) in EVG, von Willebrand factor (VWF), α-smooth muscle actin staining (αSMA) and negative controls. Photomicrographs (confocal microscopy) of a section of the intimal and plexiform lesion (Panels C), by using antibodies for VWF and αSMA, were presented. TO-PRO-3, nuclear staining. Arrows indicate abnormal cells.
Mentions: In the longitudinal and cross sections of intimal lesions, an intimal cell mass occluded the vessel lumen (Fig. 2Aab, Ba-l). VWF-positive endothelial cells formed a luminal monolayer, which covered the supporting ‘hyperchromatic and oval’ cells positive for αSMA in the intima-media complex (Fig. 2B, C). Sprouting intimal lesions, which were observed as early as 3 weeks, were associated with the fragmented internal and external elastic laminae. (Fig. 2Ab, Ba). The complex plexiform lesion, which was observed predominantly 13 weeks after initial treatment, comprised a plexus of aneurysmal and angiomatoid small vessels and supporting cellular and matrix compontents, was covered by remnants of elastic laminae. (Fig. 3A, S1A-B Fig.). The ‘sprouting’ plexiform lesion, which began to be observed even rarely as early as 3 weeks, was a focal projection originating from the parent vessel and frequently appeared to be located within an aneurismal dilatation of a side branch with fragmented elastic laminae (Fig. 2Ac, Bm, Fig. 3B, C, D). VWF-positive endothelial cells formed a monolayer on the luminal surface in the vascular channel-like structure, that was supported by αSMA+ supporting cells (Fig. 2Bm-p, C); in some complex plexiform lesions, endothelial monolayers covering vascular channel lumen were sparsely distributed and were separated by abundant αSMA+ supporting cell cluster and matrix deposition (Fig. 3A, S1C-D Fig.). αSMA+ dilatation lesions in plexiform lesions appeared to be contiguous with αSMA + media of the parent vessels, while αSMA+ supporting cells in plexiform lesions were continuous with αSMA+ supporting cells in the intima of some parent vessels (Fig. 3C, D).

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