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Collagen inhibitory peptide R1R2 mediates vascular remodeling by decreasing inflammation and smooth muscle cell activation.

Lee TH, Sottile J, Chiang HY - PLoS ONE (2015)

Bottom Line: Morphometric analysis demonstrated that R1R2 reduced intima-media thickening compared to the control groups.This decrease was accompanied by decreased VCAM-1 and ICAM-1 expression.Our in vitro studies revealed that R1R2 attenuated SMC proliferation and migration, and also decreased monocyte adhesion and transendothelial migration through endothelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.

ABSTRACT
The extracellular matrix (ECM) is a major constituent of the vessel wall. In addition to providing a structural scaffold, the ECM controls numerous cellular functions in both physiologic and pathologic settings. Vascular remodeling occurs after injury and is characterized by endothelial cell activation, inflammatory cell infiltration, phenotypic modulation of smooth muscle cells (SMCs), and augmented deposition of collagen-rich ECM. R1R2, a peptide derived from the bacterial adhesin SFS, with sequence homology to collagen, is known to inhibit collagen type I deposition in vitro by inhibiting the binding of fibronectin to collagen. However, the inhibitory effects of R1R2 during vascular remodeling have not been explored. We periadventitially delivered R1R2 to carotid arteries using pluronic gel in a vascular remodeling mouse model induced by blood flow cessation, and evaluated its effects on intima-media thickening, ECM deposition, SMC activation, and inflammatory cell infiltration. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening compared to the control groups. R1R2 treatment also decreased collagen type I deposition in the vessel wall, and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by ∼ 78%. This decrease was accompanied by decreased VCAM-1 and ICAM-1 expression. Our in vitro studies revealed that R1R2 attenuated SMC proliferation and migration, and also decreased monocyte adhesion and transendothelial migration through endothelial cells. Together, these data suggest that R1R2 attenuates vascular remodeling responses by decreasing inflammation and by modulating SMC proliferation and migration, and suggest that the R1R2 peptide may have therapeutic potential in treating occlusive vascular diseases.

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The collagen homologous peptide, R1R2, decreases vascular remodeling in the carotid artery.(A) Representative photomicrographs of the left carotid artery 14 days after ligation. Lumen (L), neointima (I) and media (M) in ligated vessels are shown. C indicates blood clot. Bar, 200 μm. Morphometric analyses of the lumen (B), intima+media (C), the external elastic lamina compartment (EEL; D), and intima/media ratio (E) 7 and 14 days after ligation. * indicates p<0.05, ** p< 0.01 and *** p< 0.001.
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pone.0117356.g002: The collagen homologous peptide, R1R2, decreases vascular remodeling in the carotid artery.(A) Representative photomicrographs of the left carotid artery 14 days after ligation. Lumen (L), neointima (I) and media (M) in ligated vessels are shown. C indicates blood clot. Bar, 200 μm. Morphometric analyses of the lumen (B), intima+media (C), the external elastic lamina compartment (EEL; D), and intima/media ratio (E) 7 and 14 days after ligation. * indicates p<0.05, ** p< 0.01 and *** p< 0.001.

Mentions: To directly test the effect of the R1R2 peptide in a model of vascular remodeling in mice, we evaluated the extent of neointimal formation in the presence or absence of the R1R2 peptide 7 days and 14 days after completely ligating the left common carotid artery in FVB mice. In this flow-induced model of vascular remodeling, neointimal formation is accompanied by significant leukocyte infiltration, proliferation of VSMCs, and extensive ECM accumulation; the endothelium remains intact [34–36]. R1R2 was periadventitially applied into carotid arteries using pluronic gel. We previously showed that a recombinant peptide can be delivered periadventitially by pluronic gel into the intima and media layers of mouse carotid artery after surgery [38]. As shown in Fig. 2A, no apparent vascular remodeling was observed in the vessels of sham-operated mice, but the experimental groups of ligation, ligation with gel alone, and ligation with scrambled peptide, revealed significant neointimal formation. There was no difference among these three groups in terms of intima-media area (Intima + Media), area bound by the external elastic lamina (EEL) and intima/media ratio at 7 and 14 days post-ligation (Fig. 2A through 2E and Table 1), indicating the pluronic gel alone and the scrambled peptide have no effect on neointimal formation. Carotid arteries treated with R1R2 peptide, however, showed a dramatic attenuation in injury-induced neointimal formation (Fig. 2A through 2E). Morphometric analyses revealed significantly reduced intima-media areas (Intima + Media), EEL area and intimal/medial ratios 7 days and 14 days after artery ligation in R1R2-treated mice as compared to the control mice (Fig. 2C through 2E and Table 1). Interestingly, there was no significant decrease in the lumenal area in the R1R2-treated vessels at day 7 and 14 after injury when compared to the controls (Fig. 2B). Taken together, our study indicates that R1R2 treatment significantly attenuates neointimal formation in ligated vessels of mice.


Collagen inhibitory peptide R1R2 mediates vascular remodeling by decreasing inflammation and smooth muscle cell activation.

Lee TH, Sottile J, Chiang HY - PLoS ONE (2015)

The collagen homologous peptide, R1R2, decreases vascular remodeling in the carotid artery.(A) Representative photomicrographs of the left carotid artery 14 days after ligation. Lumen (L), neointima (I) and media (M) in ligated vessels are shown. C indicates blood clot. Bar, 200 μm. Morphometric analyses of the lumen (B), intima+media (C), the external elastic lamina compartment (EEL; D), and intima/media ratio (E) 7 and 14 days after ligation. * indicates p<0.05, ** p< 0.01 and *** p< 0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4326127&req=5

pone.0117356.g002: The collagen homologous peptide, R1R2, decreases vascular remodeling in the carotid artery.(A) Representative photomicrographs of the left carotid artery 14 days after ligation. Lumen (L), neointima (I) and media (M) in ligated vessels are shown. C indicates blood clot. Bar, 200 μm. Morphometric analyses of the lumen (B), intima+media (C), the external elastic lamina compartment (EEL; D), and intima/media ratio (E) 7 and 14 days after ligation. * indicates p<0.05, ** p< 0.01 and *** p< 0.001.
Mentions: To directly test the effect of the R1R2 peptide in a model of vascular remodeling in mice, we evaluated the extent of neointimal formation in the presence or absence of the R1R2 peptide 7 days and 14 days after completely ligating the left common carotid artery in FVB mice. In this flow-induced model of vascular remodeling, neointimal formation is accompanied by significant leukocyte infiltration, proliferation of VSMCs, and extensive ECM accumulation; the endothelium remains intact [34–36]. R1R2 was periadventitially applied into carotid arteries using pluronic gel. We previously showed that a recombinant peptide can be delivered periadventitially by pluronic gel into the intima and media layers of mouse carotid artery after surgery [38]. As shown in Fig. 2A, no apparent vascular remodeling was observed in the vessels of sham-operated mice, but the experimental groups of ligation, ligation with gel alone, and ligation with scrambled peptide, revealed significant neointimal formation. There was no difference among these three groups in terms of intima-media area (Intima + Media), area bound by the external elastic lamina (EEL) and intima/media ratio at 7 and 14 days post-ligation (Fig. 2A through 2E and Table 1), indicating the pluronic gel alone and the scrambled peptide have no effect on neointimal formation. Carotid arteries treated with R1R2 peptide, however, showed a dramatic attenuation in injury-induced neointimal formation (Fig. 2A through 2E). Morphometric analyses revealed significantly reduced intima-media areas (Intima + Media), EEL area and intimal/medial ratios 7 days and 14 days after artery ligation in R1R2-treated mice as compared to the control mice (Fig. 2C through 2E and Table 1). Interestingly, there was no significant decrease in the lumenal area in the R1R2-treated vessels at day 7 and 14 after injury when compared to the controls (Fig. 2B). Taken together, our study indicates that R1R2 treatment significantly attenuates neointimal formation in ligated vessels of mice.

Bottom Line: Morphometric analysis demonstrated that R1R2 reduced intima-media thickening compared to the control groups.This decrease was accompanied by decreased VCAM-1 and ICAM-1 expression.Our in vitro studies revealed that R1R2 attenuated SMC proliferation and migration, and also decreased monocyte adhesion and transendothelial migration through endothelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.

ABSTRACT
The extracellular matrix (ECM) is a major constituent of the vessel wall. In addition to providing a structural scaffold, the ECM controls numerous cellular functions in both physiologic and pathologic settings. Vascular remodeling occurs after injury and is characterized by endothelial cell activation, inflammatory cell infiltration, phenotypic modulation of smooth muscle cells (SMCs), and augmented deposition of collagen-rich ECM. R1R2, a peptide derived from the bacterial adhesin SFS, with sequence homology to collagen, is known to inhibit collagen type I deposition in vitro by inhibiting the binding of fibronectin to collagen. However, the inhibitory effects of R1R2 during vascular remodeling have not been explored. We periadventitially delivered R1R2 to carotid arteries using pluronic gel in a vascular remodeling mouse model induced by blood flow cessation, and evaluated its effects on intima-media thickening, ECM deposition, SMC activation, and inflammatory cell infiltration. Morphometric analysis demonstrated that R1R2 reduced intima-media thickening compared to the control groups. R1R2 treatment also decreased collagen type I deposition in the vessel wall, and maintained SMC in the contractile phenotype. Interestingly, R1R2 dramatically reduced inflammatory cell infiltration into the vessel by ∼ 78%. This decrease was accompanied by decreased VCAM-1 and ICAM-1 expression. Our in vitro studies revealed that R1R2 attenuated SMC proliferation and migration, and also decreased monocyte adhesion and transendothelial migration through endothelial cells. Together, these data suggest that R1R2 attenuates vascular remodeling responses by decreasing inflammation and by modulating SMC proliferation and migration, and suggest that the R1R2 peptide may have therapeutic potential in treating occlusive vascular diseases.

Show MeSH
Related in: MedlinePlus