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Incongruence betwee...
Incongruence between transcriptional and vascular pathophysiological cell states
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- Fernandez-Chacon, Macarena (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.;Univ Loyola Andalucia, Fac Hlth Sci, Seville, Spain.
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- Muhleder, Severin (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Regano, Alvaro (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Garcia-Ortega, Lourdes (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Rocha, Susana F. (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Torroja, Carlos (author)
- Ctr Nacl Invest Cardiovasc CNIC, Bioinformat Unit, Madrid, Spain.
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- Sanchez-Munoz, Maria S. (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Lytvyn, Mariya (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Casquero-Garcia, Veronica (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- De Andres-Laguillo, Macarena (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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- Muhl, Lars (author)
- Karolinska Inst, Dept Med, Huddinge, Sweden.
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- Orlich, Michael M. (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden.
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- Gängel, Konstantin (author)
- Dept Immunol Genet & Pathol, Rudbeck Lab, Uppsala, Sweden.
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- Camafeita, Emilio (author)
- Ctr Nacl Invest Cardiovasc CNIC, Cardiovasc Prote Lab, Madrid, Spain.;CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain.
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- Vazquez, Jesus (author)
- Ctr Nacl Invest Cardiovasc CNIC, Cardiovasc Prote Lab, Madrid, Spain.;CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain.
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- Benguria, Alberto (author)
- Ctr Nacl Invest Cardiovasc CNIC, Genom Unit, Madrid, Spain.
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- Iruela-Arispe, M. Luisa (author)
- Northwestern Univ, Feinberg Sch Med, Dept Cell & Dev Biol, Chicago, IL USA.
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- Dopazo, Ana (author)
- CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain.;Ctr Nacl Invest Cardiovasc CNIC, Genom Unit, Madrid, Spain.
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- Sanchez-Cabo, Fatima (author)
- Ctr Nacl Invest Cardiovasc CNIC, Bioinformat Unit, Madrid, Spain.;CIBER Enfermedades Cardiovasc CIBERCV, Madrid, Spain.
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- Carter, Hannah (author)
- Univ Calif San Diego, Dept Med, Div Med Genet, La Jolla, CA USA.;Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA USA.
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- Benedito, Rui (author)
- Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain.
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Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain;Univ Loyola Andalucia, Fac Hlth Sci, Seville, Spain. Ctr Nacl Invest Cardiovasc CNIC, Mol Genet Angiogenesis Grp, Madrid, Spain. (creator_code:org_t)
- SPRINGERNATURE, 2023
- 2023
- English.
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In: NATURE CARDIOVASCULAR RESEARCH. - : SPRINGERNATURE. - 2731-0590. ; 2:6, s. 530-549
- Related links:
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https://uu.diva-port... (primary) (Raw object)
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Abstract
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- The Notch pathway is a major regulator of endothelial transcriptional specification. Targeting the Notch receptors or Delta-like ligand 4 (Dll4) dysregulates angiogenesis. Here, by analyzing single and compound genetic mutants for all Notch signaling members, we find significant differences in the way ligands and receptors regulate liver vascular homeostasis. Loss of Notch receptors caused endothelial hypermitogenic cell-cycle arrest and senescence. Conversely, Dll4 loss triggered a strong Myc-driven transcriptional switch inducing endothelial proliferation and the tip-cell state. Myc loss suppressed the induction of angiogenesis in the absence of Dll4, without preventing the vascular enlargement and organ pathology. Similarly, inhibition of other pro-angiogenic pathways, including MAPK/ERK and mTOR, had no effect on the vascular expansion induced by Dll4 loss; however, anti-VEGFA treatment prevented it without fully suppressing the transcriptional and metabolic programs. This study shows incongruence between single-cell transcriptional states, vascular phenotypes and related pathophysiology. Our findings also suggest that the vascular structure abnormalization, rather than neoplasms, causes the reported anti-Dll4 antibody toxicity. Fernandez-Chacon et al. use imaging and scRNA-seq after targeting multiple Notch genes and angiogenic signaling pathways to find that the function of these pathways in vascular pathophysiology cannot be predicted by assessing transcriptional states.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Fernandez-Chacon ...
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Muhleder, Severi ...
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Regano, Alvaro
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Garcia-Ortega, L ...
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Rocha, Susana F.
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Torroja, Carlos
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show more...
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Sanchez-Munoz, M ...
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Lytvyn, Mariya
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Casquero-Garcia, ...
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De Andres-Laguil ...
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Muhl, Lars
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Orlich, Michael ...
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Gängel, Konstant ...
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Camafeita, Emili ...
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Vazquez, Jesus
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Benguria, Albert ...
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Iruela-Arispe, M ...
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Dopazo, Ana
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Sanchez-Cabo, Fa ...
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Carter, Hannah
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Benedito, Rui
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
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NATURE CARDIOVAS ...
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Uppsala University