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TGF-ßR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue.
Zhao, Gan; Xue, Lulu; Weiner, Aaron I; Gong, Ningqiang; Adams-Tzivelekidis, Stephanie; Wong, Joanna; Gentile, Maria E; Nottingham, Ana N; Basil, Maria C; Lin, Susan M; Niethamer, Terren K; Diamond, Joshua M; Bermudez, Christian A; Cantu, Edward; Han, Xuexiang; Cao, Yaqi; Alameh, Mohamad-Gabriel; Weissman, Drew; Morrisey, Edward E; Mitchell, Michael J; Vaughan, Andrew E.
Afiliación
  • Zhao G; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Xue L; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Weiner AI; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Gong N; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Adams-Tzivelekidis S; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Wong J; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Gentile ME; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Nottingham AN; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Basil MC; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Lin SM; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Niethamer TK; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Diamond JM; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Bermudez CA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Cantu E; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Han X; Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Cao Y; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Alameh MG; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Weissman D; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Morrisey EE; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Mitchell MJ; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Vaughan AE; Penn-CHOP Lung Biology Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Sci Transl Med ; 16(732): eadg6229, 2024 Jan 31.
Article en En | MEDLINE | ID: mdl-38295183
ABSTRACT
Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-ß signaling through TGF-ßR2 (transforming growth factor-ß receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair. Loss of endothelial Tgfbr2 prevented autocrine Vegfa (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-ßR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-ß signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-ßR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-ßR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Gripe Humana Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Gripe Humana Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos