B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Disrupt Pathological Vessels?
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| Titel: | B55α/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complementary Approach To Disrupt Pathological Vessels? |
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| Autoren: | Elizabeth A. V. Jones, Donatella Ponti, Massimiliano Mazzone, Giusy Di Conza, Manuel Ehling, Sander Willox, Rosa Martín-Pérez, Maria C. Cid, Ward Celus, Roser Alba-Rovira |
| Quelle: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Dipòsit Digital de la UB instname |
| Verlagsinformationen: | Ovid Technologies (Wolters Kluwer Health), 2020. |
| Publikationsjahr: | 2020 |
| Schlagwörter: | Male, 0301 basic medicine, Cardiac & Cardiovascular Systems, p38 Mitogen-Activated Protein Kinases/metabolism, Oncologia, B55/PP2A-phosphatase, tumor progression, Angiogenesis Inhibitors, Apoptosis, Human Umbilical Vein Endothelial Cells/drug effects, Inbred C57BL, p38 Mitogen-Activated Protein Kinases, ANGIOGENESIS, ACTIVATION, Mice, Carcinoma, Lewis Lung, Protein Phosphatase 2/antagonists & inhibitors, Protein Phosphatase 2, Enzyme Inhibitors, Phosphorylation, 1102 Cardiorespiratory Medicine and Haematology, Endothelial Cells/drug effects, Enzyme Inhibitors/pharmacology, Mice, Knockout, Hypoxia-Inducible Factor-Proline Dioxygenases/genetics, 0303 health sciences, Tumor, vascular endothelial growth factor, Neovascularization, Pathologic, apoptosis, P38, PROTEIN PHOSPHATASE 2A, Hematology, VEGF, endothelial cells, PP2A, 3. Good health, Oncology, oncology, Female, Biologia del desenvolupament, 3201 Cardiovascular medicine and haematology, Life Sciences & Biomedicine, Signal Transduction, Lewis Lung/drug therapy, Knockout, INHIBITION, Breast Neoplasms, Vascular Remodeling, perfusion, Cell Line, MECHANISMS, Hypoxia-Inducible Factor-Proline Dioxygenases, Angiogenesis Inhibitors/pharmacology, blood vessels, developmental biology, 03 medical and health sciences, Breast Neoplasms/drug therapy, Cell Line, Tumor, Developmental biology, KINASE, Human Umbilical Vein Endothelial Cells, Animals, Humans, Neovascularization, Pathologic, Science & Technology, Carcinoma, 3202 Clinical sciences, Endothelial Cells, 1103 Clinical Sciences, Mice, Inbred C57BL, Peripheral Vascular Disease, Cardiovascular System & Hematology, METASTASIS, Cardiovascular System & Cardiology |
| Beschreibung: | Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. Objective: Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion, and oxygen restoration. Methods and Results: We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55α deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55α-deficient vessels. Conclusions: Our data underline a unique role of the B55α/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies. Graphical Abstract: A graphical abstract is available for this article. |
| Publikationsart: | Article |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1524-4571 0009-7330 |
| DOI: | 10.1161/circresaha.119.316071 |
| Zugangs-URL: | https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.119.316071 https://pubmed.ncbi.nlm.nih.gov/32527198 https://hdl.handle.net/2445/199448 https://cris.maastrichtuniversity.nl/en/publications/d96637ad-1fdd-4778-a8d9-ff88a0197f22 https://doi.org/10.1161/CIRCRESAHA.119.316071 https://pubmed.ncbi.nlm.nih.gov/32527198/ https://iris.unito.it/handle/2318/1782133 https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316071 https://www.ncbi.nlm.nih.gov/pubmed/32527198 https://www.narcis.nl/publication/RecordID/oai%3Acris.maastrichtuniversity.nl%3Apublications%2Fd96637ad-1fdd-4778-a8d9-ff88a0197f22 https://www.scilit.net/article/90dc76a9603b09c6a249ba2b51c4ae9b http://hdl.handle.net/2445/199448 https://hdl.handle.net/2318/1782133 https://doi.org/10.1161/CIRCRESAHA.119.316071 |
| Rights: | CC BY NC ND |
| Dokumentencode: | edsair.doi.dedup.....7d5049a857d8a7f409e8a1cea5ba5528 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | Rationale: How endothelial cells (ECs) migrate and form an immature vascular plexus has been extensively studied. Yet, mechanisms underlying vascular remodeling remain poorly established. A better understanding of these processes may lead to the design of novel therapeutic strategies complementary to current angiogenesis inhibitors. Objective: Starting from our previous observations that PP2A (protein phosphatase 2) regulates the HIF (hypoxia-inducible factor)/PHD-2 (prolyl hydroxylase 2)-constituted oxygen machinery, we hypothesized that this axis could play an important role during blood vessel formation, tissue perfusion, and oxygen restoration. Methods and Results: We show that the PP2A regulatory subunit B55α is at the crossroad between vessel pruning and vessel maturation. Blood vessels with high B55α counter cell stress conditions and thrive for stabilization and maturation. When B55α is inhibited, ECs cannot cope with cell stress and undergo apoptosis, leading to massive pruning of nascent blood vessels. Mechanistically, we found that the B55α/PP2A complex restrains PHD-2 activity, promoting EC survival in a HIF-dependent manner, and furthermore dephosphorylates p38, altogether protecting ECs against cell stress occurring, for example, during the onset of blood flow. In tumors, EC-specific B55α deficiency induces pruning of immature-like tumor blood vessels resulting in delayed tumor growth and metastasis, without affecting nonpathological vessels. Consistently, systemic administration of a pan-PP2A inhibitor disrupts vascular network formation and tumor progression in vivo without additional effects on B55α-deficient vessels. Conclusions: Our data underline a unique role of the B55α/PP2A phosphatase complex in vessel remodeling and suggest the use of PP2A-inhibitors as potent antiangiogenic drugs targeting specifically nascent blood vessels with a mode-of-action complementary to VEGF-R (vascular endothelial growth factor receptor)-targeted therapies. Graphical Abstract: A graphical abstract is available for this article. |
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| ISSN: | 15244571 00097330 |
| DOI: | 10.1161/circresaha.119.316071 |