Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells
Summary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via ju...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223007393 |
| _version_ | 1797839078558793728 |
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| author | Risa Ramadhiani Koji Ikeda Kazuya Miyagawa Gusty Rizky Tough Ryanto Naoki Tamada Yoko Suzuki Yuhei Kirita Satoaki Matoba Ken-ichi Hirata Noriaki Emoto |
| author_facet | Risa Ramadhiani Koji Ikeda Kazuya Miyagawa Gusty Rizky Tough Ryanto Naoki Tamada Yoko Suzuki Yuhei Kirita Satoaki Matoba Ken-ichi Hirata Noriaki Emoto |
| author_sort | Risa Ramadhiani |
| collection | DOAJ |
| description | Summary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly. |
| first_indexed | 2024-04-09T15:52:25Z |
| format | Article |
| id | doaj.art-df22407a34e84d789aea5a435293864b |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T15:52:25Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-df22407a34e84d789aea5a435293864b2023-04-26T06:00:42ZengElsevieriScience2589-00422023-05-01265106662Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cellsRisa Ramadhiani0Koji Ikeda1Kazuya Miyagawa2Gusty Rizky Tough Ryanto3Naoki Tamada4Yoko Suzuki5Yuhei Kirita6Satoaki Matoba7Ken-ichi Hirata8Noriaki Emoto9Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, JapanLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Department of Epidemiology for Longevity and Regional Health, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan; Department of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, Japan; Corresponding authorLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, JapanLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, JapanLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, JapanLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, JapanDepartment of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, JapanDepartment of Cardiology and Nephrology, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyou, Kyoto 6028566, JapanDivision of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, JapanLaboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada, Kobe 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe 6500017, Japan; Corresponding authorSummary: Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.http://www.sciencedirect.com/science/article/pii/S2589004223007393Biological sciencesMolecular biologyCell biology |
| spellingShingle | Risa Ramadhiani Koji Ikeda Kazuya Miyagawa Gusty Rizky Tough Ryanto Naoki Tamada Yoko Suzuki Yuhei Kirita Satoaki Matoba Ken-ichi Hirata Noriaki Emoto Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells iScience Biological sciences Molecular biology Cell biology |
| title | Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| title_full | Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| title_fullStr | Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| title_full_unstemmed | Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| title_short | Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells |
| title_sort | endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine notch signaling in smooth muscle cells |
| topic | Biological sciences Molecular biology Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223007393 |
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