Abstract
Objective:
Adventitia acts as an active participant in vascular inflammation but the precise mechanism underlying adventitia-mediated vascular inflammation is not fully understood. In this study, we sought to determine whether vascular endothelial growth factor (VEGF) regulates osteopontin (OPN) expression through Flt-1 in adventitial fibroblasts (AFs) to mediate vascular inflammation and neointima formation.
Methods and results:
In primary cultured AFs, VEGF increased intracellular and secreted OPN expression in a time- and dose-dependent manner, which was effectively suppressed by a specific anti-Flt-1 hexapeptide. Interestingly, VEGF treatment of AFs enhanced the capability of AF-conditioned medium to stimulate macrophages chemotaxis, and this effect was attenuated after blockade of OPN from AF-conditioned medium. Furthermore, perivascular delivery of anti-Flt-1 peptide preferentially concentrated in the adventitia resulted in a decrease of neointima formation after balloon injury in carotid arteries. The inhibition of neointima formation was preceded by significant reduction of VEGF and OPN expression with concurrent macrophage infiltration into adventitia after injury. Activation of extracellular signal-regulated kinase 1/2 pathway was involved in OPN upregulation and macrophage chemotaxis.
Conclusions:
These results demonstrate that VEGF/Flt-1 signaling plays a significant role in vascular inflammation and neointima formation by regulating OPN expression in AFs and provide insight into Flt-1 as a potential therapeutic target for vascular diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta, Thoracic / immunology
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Aorta, Thoracic / metabolism
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Aorta, Thoracic / pathology
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Carotid Artery Injuries / immunology
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Carotid Artery Injuries / metabolism*
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Carotid Artery Injuries / pathology
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Carotid Artery, Common / immunology
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Carotid Artery, Common / metabolism
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Carotid Artery, Common / pathology
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Cell Line
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Cell Proliferation
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Chemotaxis
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Connective Tissue / drug effects
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Connective Tissue / immunology
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Connective Tissue / metabolism*
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Connective Tissue / pathology
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Disease Models, Animal
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Fibroblasts / immunology
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Inflammation / immunology
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Inflammation / metabolism*
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Inflammation / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neointima
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Oligopeptides / pharmacology
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Osteopontin / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Rats
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Rats, Sprague-Dawley
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Signal Transduction
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Time Factors
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Up-Regulation
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-1 / metabolism*
Substances
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Oligopeptides
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Protein Kinase Inhibitors
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Spp1 protein, rat
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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Osteopontin
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Flt1 protein, rat
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Vascular Endothelial Growth Factor Receptor-1
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Mapk1 protein, rat
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3