Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation
Background Vascular restenosis resulting from neointima formation significantly limits the efficacy of percutaneous interventional therapies compared with bypass surgery. The adventitial layer is involved in neointima formation, but the detailed pathophysiological interplay of the different cell typ...
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Wiley
2025-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.040143 |
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| author | Jochen Dutzmann Jan‐Marcus Daniel Laura Korte Frederik J. Kloss Kai Knöpp Katrin Kalies Kevin J. Croce Thomas J. Herbst Barbara Huibregtse Felix J. Vogt Stefan Offermanns Johann Bauersachs Daniel G. Sedding |
| author_facet | Jochen Dutzmann Jan‐Marcus Daniel Laura Korte Frederik J. Kloss Kai Knöpp Katrin Kalies Kevin J. Croce Thomas J. Herbst Barbara Huibregtse Felix J. Vogt Stefan Offermanns Johann Bauersachs Daniel G. Sedding |
| author_sort | Jochen Dutzmann |
| collection | DOAJ |
| description | Background Vascular restenosis resulting from neointima formation significantly limits the efficacy of percutaneous interventional therapies compared with bypass surgery. The adventitial layer is involved in neointima formation, but the detailed pathophysiological interplay of the different cell types in this process is still unclear. Methods We analyzed the correlation between adventitial and neointimal tissue size in human postmortem restenotic lesions after angioplasty. In porcine and mouse models of vascular injury, we examined early proliferation of fibroblasts and adventitial expansion. Using anti‐CD45 antibodies, we identified recruited leukocytes as the source of fibroblast activation following vascular injury in mice. A time‐course experiment on neointima formation demonstrated that adventitial activation precedes the proliferation of medial and neointimal smooth muscle cells (SMCs). To further investigate this process, we developed a mouse model enabling the surgical removal and transplantation of adventitial tissue. Results We observed that activated adventitial fibroblasts release interleukin 6 and other cytokines, which strongly induce SMC proliferation and migration in vitro. In interleukin 6 knockout mice, supernatants from activated adventitia grafts failed to stimulate SMC proliferation and migration. Furthermore, transplantation of adventitial grafts from interleukin 6 knockout mice did not induce neointima formation. Cell fate tracking experiments using double transgenic reporter mice demonstrated that resident adventitial cells do not directly contribute to the neointimal cellular mass. Instead, medial SMCs were identified as the primary source of neointimal cells. Conclusions We show that the release of interleukin 6 by adventitial fibroblasts induces the subsequent proliferation and migration of medial SMC in the process of neointima formation. Thus, we propose a new paradigm for adventitial fibroblasts in this process as a paracrine inflammatory engine. Anti‐inflammatory targeting of the vascular adventitia might thus be promising to limit neointima formation. |
| format | Article |
| id | doaj-art-334a3d5001d540c1943a6660ffd5a0f3 |
| institution | Kabale University |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-334a3d5001d540c1943a6660ffd5a0f32025-08-20T03:50:49ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-07-01141410.1161/JAHA.124.040143Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima FormationJochen Dutzmann0Jan‐Marcus Daniel1Laura Korte2Frederik J. Kloss3Kai Knöpp4Katrin Kalies5Kevin J. Croce6Thomas J. Herbst7Barbara Huibregtse8Felix J. Vogt9Stefan Offermanns10Johann Bauersachs11Daniel G. Sedding12Mid‐German Heart Center, Division of Cardiology, Vascular Medicine, and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle‐Wittenberg Halle GermanyMid‐German Heart Center, Division of Cardiology, Vascular Medicine, and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle‐Wittenberg Halle GermanyDepartment of Cardiology and Angiology Hannover Medical School Hannover GermanyDepartment of Cardiology and Angiology Hannover Medical School Hannover GermanyMid‐German Heart Center, Division of Cardiology, Vascular Medicine, and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle‐Wittenberg Halle GermanyMid‐German Heart Center, Division of Cardiology, Vascular Medicine, and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle‐Wittenberg Halle GermanyCardiovascular Division, Department of Medicine Harvard Medical School, Brigham and Women’s Hospital Boston MA USAPreclinical Sciences Boston Scientific Corporation Inc. Natick MA USAPreclinical Sciences Boston Scientific Corporation Inc. Natick MA USADepartment of Cardiology, Pneumology, Angiology, and Internal Intensive Medicine University Hospital Aachen Aachen GermanyDepartment of Pharmacology Max‐Planck‐Institute for Heart and Lung Research Bad Nauheim GermanyDepartment of Cardiology and Angiology Hannover Medical School Hannover GermanyMid‐German Heart Center, Division of Cardiology, Vascular Medicine, and Intensive Medical Care University Hospital Halle, Martin‐Luther‐University Halle‐Wittenberg Halle GermanyBackground Vascular restenosis resulting from neointima formation significantly limits the efficacy of percutaneous interventional therapies compared with bypass surgery. The adventitial layer is involved in neointima formation, but the detailed pathophysiological interplay of the different cell types in this process is still unclear. Methods We analyzed the correlation between adventitial and neointimal tissue size in human postmortem restenotic lesions after angioplasty. In porcine and mouse models of vascular injury, we examined early proliferation of fibroblasts and adventitial expansion. Using anti‐CD45 antibodies, we identified recruited leukocytes as the source of fibroblast activation following vascular injury in mice. A time‐course experiment on neointima formation demonstrated that adventitial activation precedes the proliferation of medial and neointimal smooth muscle cells (SMCs). To further investigate this process, we developed a mouse model enabling the surgical removal and transplantation of adventitial tissue. Results We observed that activated adventitial fibroblasts release interleukin 6 and other cytokines, which strongly induce SMC proliferation and migration in vitro. In interleukin 6 knockout mice, supernatants from activated adventitia grafts failed to stimulate SMC proliferation and migration. Furthermore, transplantation of adventitial grafts from interleukin 6 knockout mice did not induce neointima formation. Cell fate tracking experiments using double transgenic reporter mice demonstrated that resident adventitial cells do not directly contribute to the neointimal cellular mass. Instead, medial SMCs were identified as the primary source of neointimal cells. Conclusions We show that the release of interleukin 6 by adventitial fibroblasts induces the subsequent proliferation and migration of medial SMC in the process of neointima formation. Thus, we propose a new paradigm for adventitial fibroblasts in this process as a paracrine inflammatory engine. Anti‐inflammatory targeting of the vascular adventitia might thus be promising to limit neointima formation.https://www.ahajournals.org/doi/10.1161/JAHA.124.040143adventitial fibroblastsinterleukin 6neointima formationparacrine signalingsmooth muscle cellsvascular restenosis |
| spellingShingle | Jochen Dutzmann Jan‐Marcus Daniel Laura Korte Frederik J. Kloss Kai Knöpp Katrin Kalies Kevin J. Croce Thomas J. Herbst Barbara Huibregtse Felix J. Vogt Stefan Offermanns Johann Bauersachs Daniel G. Sedding Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease adventitial fibroblasts interleukin 6 neointima formation paracrine signaling smooth muscle cells vascular restenosis |
| title | Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation |
| title_full | Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation |
| title_fullStr | Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation |
| title_full_unstemmed | Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation |
| title_short | Adventitial Fibroblasts Release Interleukin 6 After Vascular Injury and Induce Smooth Muscle Cell Proliferation and Neointima Formation |
| title_sort | adventitial fibroblasts release interleukin 6 after vascular injury and induce smooth muscle cell proliferation and neointima formation |
| topic | adventitial fibroblasts interleukin 6 neointima formation paracrine signaling smooth muscle cells vascular restenosis |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.040143 |
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