Elastogenic inductability of smooth muscle cells from a rat model of late stage abdominal aortic aneurysms.
Identifieur interne : 000814 ( Ncbi/Curation ); précédent : 000813; suivant : 000815Elastogenic inductability of smooth muscle cells from a rat model of late stage abdominal aortic aneurysms.
Auteurs : Carmen E. Gacchina [États-Unis] ; Partha Deb ; Jeremy L. Barth ; Anand RamamurthiSource :
- Tissue engineering. Part A [ 1937-335X ] ; 2011.
Descripteurs français
- KwdFr :
- Analyse de profil d'expression de gènes, Animaux, Anévrysme de l'aorte abdominale (anatomopathologie), Aorte (), Aorte (anatomopathologie), Aorte (ultrastructure), Coloration et marquage, Facteur de croissance transformant bêta (pharmacologie), Humains, Matrice extracellulaire (métabolisme), Matrice extracellulaire (ultrastructure), Maturation post-traductionnelle des protéines (), Modèles animaux de maladie humaine, Myocytes du muscle lisse (), Myocytes du muscle lisse (anatomopathologie), Myocytes du muscle lisse (ultrastructure), Mâle, Pancreatic elastase (métabolisme), Perfusion, Phénotype, Prolifération cellulaire (), Rat Sprague-Dawley, Rats, Régulation de l'expression des gènes (), Sus scrofa, Séquençage par oligonucléotides en batterie, Technique d'immunofluorescence, Élastine (métabolisme), Élastine (ultrastructure), Évolution de la maladie.
- MESH :
- anatomopathologie : Anévrysme de l'aorte abdominale, Aorte, Myocytes du muscle lisse.
- métabolisme : Matrice extracellulaire, Pancreatic elastase, Élastine.
- pharmacologie : Facteur de croissance transformant bêta.
- Analyse de profil d'expression de gènes, Animaux, Aorte, Coloration et marquage, Humains, Matrice extracellulaire, Maturation post-traductionnelle des protéines, Modèles animaux de maladie humaine, Myocytes du muscle lisse, Mâle, Perfusion, Phénotype, Prolifération cellulaire, Rat Sprague-Dawley, Rats, Régulation de l'expression des gènes, Sus scrofa, Séquençage par oligonucléotides en batterie, Technique d'immunofluorescence, Élastine, Évolution de la maladie.
English descriptors
- KwdEn :
- Animals, Aorta (drug effects), Aorta (pathology), Aorta (ultrastructure), Aortic Aneurysm, Abdominal (pathology), Cell Proliferation (drug effects), Disease Models, Animal, Disease Progression, Elastin (metabolism), Elastin (ultrastructure), Extracellular Matrix (metabolism), Extracellular Matrix (ultrastructure), Fluorescent Antibody Technique, Gene Expression Profiling, Gene Expression Regulation (drug effects), Humans, Male, Myocytes, Smooth Muscle (drug effects), Myocytes, Smooth Muscle (pathology), Myocytes, Smooth Muscle (ultrastructure), Oligonucleotide Array Sequence Analysis, Pancreatic Elastase (metabolism), Perfusion, Phenotype, Protein Processing, Post-Translational (drug effects), Rats, Rats, Sprague-Dawley, Staining and Labeling, Sus scrofa, Transforming Growth Factor beta (pharmacology).
- MESH :
- chemical , metabolism : Elastin, Pancreatic Elastase.
- drug effects : Aorta, Cell Proliferation, Gene Expression Regulation, Myocytes, Smooth Muscle, Protein Processing, Post-Translational.
- metabolism : Extracellular Matrix.
- pathology : Aorta, Aortic Aneurysm, Abdominal, Myocytes, Smooth Muscle.
- chemical , pharmacology : Transforming Growth Factor beta.
- ultrastructure : Aorta, Elastin, Extracellular Matrix, Myocytes, Smooth Muscle.
- Animals, Disease Models, Animal, Disease Progression, Fluorescent Antibody Technique, Gene Expression Profiling, Humans, Male, Oligonucleotide Array Sequence Analysis, Perfusion, Phenotype, Rats, Rats, Sprague-Dawley, Staining and Labeling, Sus scrofa.
Abstract
Although abdominal aortic aneurysms (AAA) can be potentially stabilized by inhibiting inflammatory cell recruitment and their release of proteolytic enzymes, active AAA regression is not possible without regeneration of new elastic matrix structures. Unfortunately, postneonatal vascular smooth muscle cells (SMCs), healthy, and likely more so, diseased cells, poorly synthesize or remodel elastic fibers, impeding any effort directed at regenerative AAA treatment. Previously, we determined the eleastogenic benefits of oligomers (HA-o; 4-6 mers) of the glycosaminoglycan, hyaluronan (HA) and transforming growth factor-β1 (TGF-β1) to healthy SMCs. Since AAAs are often diagnosed only late in development when matrix disruption is severe, we now determine if elastogenic upregulation of SMCs from late-stage AAAs (>100% diameter increase) is possible. AAAs were induced by perfusion of rat infrarenal aortae with porcine pancreatic elastase. Elastic matrix degradation, vessel expansion (∼120%), inflammatory cell infiltration, and enhanced activity of matrix-metalloproteases (MMPs) 2 and 9 resulted, paralleling human AAAs. Aneurysmal SMCs (EaRASMCs) maintained a diseased phenotype in 2D cell culture and exhibited patterns of gene expression different from healthy rat aortic SMCs (RASMCs). Relative to passage-matched healthy RASMCs, unstimulated EaRASMCs produced far less tropoelastin and matrix elastin. Exogenous TGF-β and HA-o (termed "factors") significantly decreased EaRASMC proliferation and enhanced tropoelastin synthesis, though only at the highest provided dose combination (20 mg/mL of HA-o, 10 ng/mL of TGF-β); despite such enhancement, tropoelastin amounts were only ∼40% of amounts synthesized by healthy RASMC cultures. Differently, elastic matrix synthesis was enhanced beyond amounts synthesized by healthy RASMCs (112%), even at lower doses of factors (2 mg/mL of HA-o and 5 ng/mL of TGF-β). The factors also enhanced elastic fiber deposition over untreated EaRASMC cultures and restored several genes whose expression was altered in EaRASMC cultures back to levels expressed by healthy RASMCs. However, the activity of MMPs 2 and 9 generated by EaRASMC cultures was unaffected by the factors/factor dose. The study confirms that SMCs from advanced AAAs can be elastogenically induced, although much higher doses of elastogenic factors are required for induction relative to healthy SMCs. Also, the factors do not appear to inhibit MMP activity, vital to preserve existing elastic matrix structures that serve as nucleation sites for new elastic fiber deposition. Thus, to enhance net accumulation of newly regenerated elastic matrix, toward possibly regressing AAAs, codelivery of MMP inhibitors may be necessitated.
DOI: 10.1089/ten.TEA.2010.0526
PubMed: 21341992
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pubmed:21341992Le document en format XML
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<author><name sortKey="Gacchina, Carmen E" sort="Gacchina, Carmen E" uniqKey="Gacchina C" first="Carmen E" last="Gacchina">Carmen E. Gacchina</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Clinical Center, National Institutes of Health, Bethesda, Maryland</wicri:regionArea>
<placeName><region type="state">Maryland</region>
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<author><name sortKey="Deb, Partha" sort="Deb, Partha" uniqKey="Deb P" first="Partha" last="Deb">Partha Deb</name>
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<author><name sortKey="Barth, Jeremy L" sort="Barth, Jeremy L" uniqKey="Barth J" first="Jeremy L" last="Barth">Jeremy L. Barth</name>
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<author><name sortKey="Ramamurthi, Anand" sort="Ramamurthi, Anand" uniqKey="Ramamurthi A" first="Anand" last="Ramamurthi">Anand Ramamurthi</name>
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<author><name sortKey="Barth, Jeremy L" sort="Barth, Jeremy L" uniqKey="Barth J" first="Jeremy L" last="Barth">Jeremy L. Barth</name>
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<series><title level="j">Tissue engineering. Part A</title>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Aorta (drug effects)</term>
<term>Aorta (pathology)</term>
<term>Aorta (ultrastructure)</term>
<term>Aortic Aneurysm, Abdominal (pathology)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Disease Models, Animal</term>
<term>Disease Progression</term>
<term>Elastin (metabolism)</term>
<term>Elastin (ultrastructure)</term>
<term>Extracellular Matrix (metabolism)</term>
<term>Extracellular Matrix (ultrastructure)</term>
<term>Fluorescent Antibody Technique</term>
<term>Gene Expression Profiling</term>
<term>Gene Expression Regulation (drug effects)</term>
<term>Humans</term>
<term>Male</term>
<term>Myocytes, Smooth Muscle (drug effects)</term>
<term>Myocytes, Smooth Muscle (pathology)</term>
<term>Myocytes, Smooth Muscle (ultrastructure)</term>
<term>Oligonucleotide Array Sequence Analysis</term>
<term>Pancreatic Elastase (metabolism)</term>
<term>Perfusion</term>
<term>Phenotype</term>
<term>Protein Processing, Post-Translational (drug effects)</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
<term>Staining and Labeling</term>
<term>Sus scrofa</term>
<term>Transforming Growth Factor beta (pharmacology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Anévrysme de l'aorte abdominale (anatomopathologie)</term>
<term>Aorte ()</term>
<term>Aorte (anatomopathologie)</term>
<term>Aorte (ultrastructure)</term>
<term>Coloration et marquage</term>
<term>Facteur de croissance transformant bêta (pharmacologie)</term>
<term>Humains</term>
<term>Matrice extracellulaire (métabolisme)</term>
<term>Matrice extracellulaire (ultrastructure)</term>
<term>Maturation post-traductionnelle des protéines ()</term>
<term>Modèles animaux de maladie humaine</term>
<term>Myocytes du muscle lisse ()</term>
<term>Myocytes du muscle lisse (anatomopathologie)</term>
<term>Myocytes du muscle lisse (ultrastructure)</term>
<term>Mâle</term>
<term>Pancreatic elastase (métabolisme)</term>
<term>Perfusion</term>
<term>Phénotype</term>
<term>Prolifération cellulaire ()</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Régulation de l'expression des gènes ()</term>
<term>Sus scrofa</term>
<term>Séquençage par oligonucléotides en batterie</term>
<term>Technique d'immunofluorescence</term>
<term>Élastine (métabolisme)</term>
<term>Élastine (ultrastructure)</term>
<term>Évolution de la maladie</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Elastin</term>
<term>Pancreatic Elastase</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Anévrysme de l'aorte abdominale</term>
<term>Aorte</term>
<term>Myocytes du muscle lisse</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Aorta</term>
<term>Cell Proliferation</term>
<term>Gene Expression Regulation</term>
<term>Myocytes, Smooth Muscle</term>
<term>Protein Processing, Post-Translational</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Extracellular Matrix</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Matrice extracellulaire</term>
<term>Pancreatic elastase</term>
<term>Élastine</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Aorta</term>
<term>Aortic Aneurysm, Abdominal</term>
<term>Myocytes, Smooth Muscle</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Facteur de croissance transformant bêta</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Transforming Growth Factor beta</term>
</keywords>
<keywords scheme="MESH" qualifier="ultrastructure" xml:lang="en"><term>Aorta</term>
<term>Elastin</term>
<term>Extracellular Matrix</term>
<term>Myocytes, Smooth Muscle</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Disease Models, Animal</term>
<term>Disease Progression</term>
<term>Fluorescent Antibody Technique</term>
<term>Gene Expression Profiling</term>
<term>Humans</term>
<term>Male</term>
<term>Oligonucleotide Array Sequence Analysis</term>
<term>Perfusion</term>
<term>Phenotype</term>
<term>Rats</term>
<term>Rats, Sprague-Dawley</term>
<term>Staining and Labeling</term>
<term>Sus scrofa</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Analyse de profil d'expression de gènes</term>
<term>Animaux</term>
<term>Aorte</term>
<term>Coloration et marquage</term>
<term>Humains</term>
<term>Matrice extracellulaire</term>
<term>Maturation post-traductionnelle des protéines</term>
<term>Modèles animaux de maladie humaine</term>
<term>Myocytes du muscle lisse</term>
<term>Mâle</term>
<term>Perfusion</term>
<term>Phénotype</term>
<term>Prolifération cellulaire</term>
<term>Rat Sprague-Dawley</term>
<term>Rats</term>
<term>Régulation de l'expression des gènes</term>
<term>Sus scrofa</term>
<term>Séquençage par oligonucléotides en batterie</term>
<term>Technique d'immunofluorescence</term>
<term>Élastine</term>
<term>Évolution de la maladie</term>
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<front><div type="abstract" xml:lang="en">Although abdominal aortic aneurysms (AAA) can be potentially stabilized by inhibiting inflammatory cell recruitment and their release of proteolytic enzymes, active AAA regression is not possible without regeneration of new elastic matrix structures. Unfortunately, postneonatal vascular smooth muscle cells (SMCs), healthy, and likely more so, diseased cells, poorly synthesize or remodel elastic fibers, impeding any effort directed at regenerative AAA treatment. Previously, we determined the eleastogenic benefits of oligomers (HA-o; 4-6 mers) of the glycosaminoglycan, hyaluronan (HA) and transforming growth factor-β1 (TGF-β1) to healthy SMCs. Since AAAs are often diagnosed only late in development when matrix disruption is severe, we now determine if elastogenic upregulation of SMCs from late-stage AAAs (>100% diameter increase) is possible. AAAs were induced by perfusion of rat infrarenal aortae with porcine pancreatic elastase. Elastic matrix degradation, vessel expansion (∼120%), inflammatory cell infiltration, and enhanced activity of matrix-metalloproteases (MMPs) 2 and 9 resulted, paralleling human AAAs. Aneurysmal SMCs (EaRASMCs) maintained a diseased phenotype in 2D cell culture and exhibited patterns of gene expression different from healthy rat aortic SMCs (RASMCs). Relative to passage-matched healthy RASMCs, unstimulated EaRASMCs produced far less tropoelastin and matrix elastin. Exogenous TGF-β and HA-o (termed "factors") significantly decreased EaRASMC proliferation and enhanced tropoelastin synthesis, though only at the highest provided dose combination (20 mg/mL of HA-o, 10 ng/mL of TGF-β); despite such enhancement, tropoelastin amounts were only ∼40% of amounts synthesized by healthy RASMC cultures. Differently, elastic matrix synthesis was enhanced beyond amounts synthesized by healthy RASMCs (112%), even at lower doses of factors (2 mg/mL of HA-o and 5 ng/mL of TGF-β). The factors also enhanced elastic fiber deposition over untreated EaRASMC cultures and restored several genes whose expression was altered in EaRASMC cultures back to levels expressed by healthy RASMCs. However, the activity of MMPs 2 and 9 generated by EaRASMC cultures was unaffected by the factors/factor dose. The study confirms that SMCs from advanced AAAs can be elastogenically induced, although much higher doses of elastogenic factors are required for induction relative to healthy SMCs. Also, the factors do not appear to inhibit MMP activity, vital to preserve existing elastic matrix structures that serve as nucleation sites for new elastic fiber deposition. Thus, to enhance net accumulation of newly regenerated elastic matrix, toward possibly regressing AAAs, codelivery of MMP inhibitors may be necessitated.</div>
</front>
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