MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors
BackgroundClassical cardiovascular risk factors (CRFs) are associated with impaired angiogenic activities of bone marrow–derived proangiogenic cells (PACs) related to peripheral artery diseases (PADs) and ischemia-induced neovascularization. MicroRNAs (miRs) are key regulators of gene expression, an...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-08-01
|
| Series: | Frontiers in Genetics |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2020.00947/full |
| _version_ | 1818329058109292544 |
|---|---|
| author | Michel Desjarlais Michel Desjarlais Sylvie Dussault José Carlos Rivera José Carlos Rivera Sylvain Chemtob Sylvain Chemtob Alain Rivard |
| author_facet | Michel Desjarlais Michel Desjarlais Sylvie Dussault José Carlos Rivera José Carlos Rivera Sylvain Chemtob Sylvain Chemtob Alain Rivard |
| author_sort | Michel Desjarlais |
| collection | DOAJ |
| description | BackgroundClassical cardiovascular risk factors (CRFs) are associated with impaired angiogenic activities of bone marrow–derived proangiogenic cells (PACs) related to peripheral artery diseases (PADs) and ischemia-induced neovascularization. MicroRNAs (miRs) are key regulators of gene expression, and they are involved in the modulation of PAC function and PAC paracrine activity. However, the effects of CRFs on the modulation of miR expression in PACs are unknown.Aims and MethodsWe used a model of hindlimb ischemia and next-generation sequencing to perform a complete profiling of miRs in PACs isolated from the bone marrow of mice subjected to three models of CRFs: aging, smoking (SMK) and hypercholesterolemia (HC).ResultsApproximately 570 miRs were detected in PACs in the different CRF models. When excluding miRs with a very low expression level (<100 RPM), 40 to 61 miRs were found to be significantly modulated by aging, SMK, or HC. In each CRF condition, we identified downregulated proangiogenic miRs and upregulated antiangiogenic miRs that could contribute to explain PAC dysfunction. Interestingly, several miRs were similarly downregulated (e.g., miR-542-3p, miR-29) or upregulated (e.g., miR-501, miR-92a) in all CRF conditions. In silico approaches including Kyoto Encyclopedia of Genes and Genomes and cluster dendogram analyses identified predictive effects of these miRs on pathways having key roles in the modulation of angiogenesis and PAC function, including vascular endothelial growth factor signaling, extracellular matrix remodeling, PI3K/AKT/MAPK signaling, transforming growth factor beta (TGFb) pathway, p53, and cell cycle progression.ConclusionThis study describes for the first time the effects of CRFs on the modulation of miR profile in PACs related to PAD and ischemia-induced neovascularization. We found that several angiogenesis-modulating miRs are similarly altered in different CRF conditions. Our findings constitute a solid framework for the identification of miRs that could be targeted in PACs in order to improve their angiogenic function and for the future development of novel therapies to improve neovascularization and reduce tissue damage in patients with severe PAD. |
| first_indexed | 2024-12-13T12:42:01Z |
| format | Article |
| id | doaj.art-0356c733f27a4237a1d3977eb7b88125 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-13T12:42:01Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Genetics |
| spelling | doaj.art-0356c733f27a4237a1d3977eb7b881252022-12-21T23:45:36ZengFrontiers Media S.A.Frontiers in Genetics1664-80212020-08-011110.3389/fgene.2020.00947551628MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk FactorsMichel Desjarlais0Michel Desjarlais1Sylvie Dussault2José Carlos Rivera3José Carlos Rivera4Sylvain Chemtob5Sylvain Chemtob6Alain Rivard7Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC, CanadaDepartment of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, CanadaDepartment of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC, CanadaDepartment of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, CanadaDepartments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, CanadaDepartment of Ophthalmology, Maisonneuve-Rosemont Hospital Research Center, University of Montréal, Montréal, QC, CanadaDepartments of Pediatrics, Ophthalmology and Pharmacology, Centre Hospitalier Universitaire Sainte-Justine Research Center, Montréal, QC, CanadaDepartment of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM) Research Center, Montréal, QC, CanadaBackgroundClassical cardiovascular risk factors (CRFs) are associated with impaired angiogenic activities of bone marrow–derived proangiogenic cells (PACs) related to peripheral artery diseases (PADs) and ischemia-induced neovascularization. MicroRNAs (miRs) are key regulators of gene expression, and they are involved in the modulation of PAC function and PAC paracrine activity. However, the effects of CRFs on the modulation of miR expression in PACs are unknown.Aims and MethodsWe used a model of hindlimb ischemia and next-generation sequencing to perform a complete profiling of miRs in PACs isolated from the bone marrow of mice subjected to three models of CRFs: aging, smoking (SMK) and hypercholesterolemia (HC).ResultsApproximately 570 miRs were detected in PACs in the different CRF models. When excluding miRs with a very low expression level (<100 RPM), 40 to 61 miRs were found to be significantly modulated by aging, SMK, or HC. In each CRF condition, we identified downregulated proangiogenic miRs and upregulated antiangiogenic miRs that could contribute to explain PAC dysfunction. Interestingly, several miRs were similarly downregulated (e.g., miR-542-3p, miR-29) or upregulated (e.g., miR-501, miR-92a) in all CRF conditions. In silico approaches including Kyoto Encyclopedia of Genes and Genomes and cluster dendogram analyses identified predictive effects of these miRs on pathways having key roles in the modulation of angiogenesis and PAC function, including vascular endothelial growth factor signaling, extracellular matrix remodeling, PI3K/AKT/MAPK signaling, transforming growth factor beta (TGFb) pathway, p53, and cell cycle progression.ConclusionThis study describes for the first time the effects of CRFs on the modulation of miR profile in PACs related to PAD and ischemia-induced neovascularization. We found that several angiogenesis-modulating miRs are similarly altered in different CRF conditions. Our findings constitute a solid framework for the identification of miRs that could be targeted in PACs in order to improve their angiogenic function and for the future development of novel therapies to improve neovascularization and reduce tissue damage in patients with severe PAD.https://www.frontiersin.org/article/10.3389/fgene.2020.00947/fullmicroRNA (miR)proangiogenic cell (PAC)cardiovascular risk factorshindlimb ischemianeovascularization |
| spellingShingle | Michel Desjarlais Michel Desjarlais Sylvie Dussault José Carlos Rivera José Carlos Rivera Sylvain Chemtob Sylvain Chemtob Alain Rivard MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors Frontiers in Genetics microRNA (miR) proangiogenic cell (PAC) cardiovascular risk factors hindlimb ischemia neovascularization |
| title | MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors |
| title_full | MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors |
| title_fullStr | MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors |
| title_full_unstemmed | MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors |
| title_short | MicroRNA Expression Profiling of Bone Marrow–Derived Proangiogenic Cells (PACs) in a Mouse Model of Hindlimb Ischemia: Modulation by Classical Cardiovascular Risk Factors |
| title_sort | microrna expression profiling of bone marrow derived proangiogenic cells pacs in a mouse model of hindlimb ischemia modulation by classical cardiovascular risk factors |
| topic | microRNA (miR) proangiogenic cell (PAC) cardiovascular risk factors hindlimb ischemia neovascularization |
| url | https://www.frontiersin.org/article/10.3389/fgene.2020.00947/full |
| work_keys_str_mv | AT micheldesjarlais micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT micheldesjarlais micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT sylviedussault micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT josecarlosrivera micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT josecarlosrivera micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT sylvainchemtob micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT sylvainchemtob micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors AT alainrivard micrornaexpressionprofilingofbonemarrowderivedproangiogeniccellspacsinamousemodelofhindlimbischemiamodulationbyclassicalcardiovascularriskfactors |