TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue
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-β signaling through TGF-βR2 (transforming growth factor-β 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-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-βR2 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
|---|---|
| Enthalten in: |
Science translational medicine - 16(2024), 732 vom: 31. Jan., Seite eadg6229 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhao, Gan [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 2.7.11.30 |
|---|
| Anmerkungen: |
Date Completed 02.02.2024 Date Revised 20.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1126/scitranslmed.adg6229 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367855062 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367855062 | ||
| 003 | DE-627 | ||
| 005 | 20240220232249.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240201s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1126/scitranslmed.adg6229 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1300.xml |
| 035 | |a (DE-627)NLM367855062 | ||
| 035 | |a (NLM)38295183 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhao, Gan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 02.02.2024 | ||
| 500 | |a Date Revised 20.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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-β signaling through TGF-βR2 (transforming growth factor-β 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-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-βR2 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Receptor, Transforming Growth Factor-beta Type II |2 NLM | |
| 650 | 7 | |a EC 2.7.11.30 |2 NLM | |
| 650 | 7 | |a Vascular Endothelial Growth Factor A |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 700 | 1 | |a Xue, Lulu |e verfasserin |4 aut | |
| 700 | 1 | |a Weiner, Aaron I |e verfasserin |4 aut | |
| 700 | 1 | |a Gong, Ningqiang |e verfasserin |4 aut | |
| 700 | 1 | |a Adams-Tzivelekidis, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Joanna |e verfasserin |4 aut | |
| 700 | 1 | |a Gentile, Maria E |e verfasserin |4 aut | |
| 700 | 1 | |a Nottingham, Ana N |e verfasserin |4 aut | |
| 700 | 1 | |a Basil, Maria C |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Susan M |e verfasserin |4 aut | |
| 700 | 1 | |a Niethamer, Terren K |e verfasserin |4 aut | |
| 700 | 1 | |a Diamond, Joshua M |e verfasserin |4 aut | |
| 700 | 1 | |a Bermudez, Christian A |e verfasserin |4 aut | |
| 700 | 1 | |a Cantu, Edward |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Xuexiang |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Yaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Alameh, Mohamad-Gabriel |e verfasserin |4 aut | |
| 700 | 1 | |a Weissman, Drew |e verfasserin |4 aut | |
| 700 | 1 | |a Morrisey, Edward E |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Vaughan, Andrew E |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Science translational medicine |d 2009 |g 16(2024), 732 vom: 31. Jan., Seite eadg6229 |w (DE-627)NLM195151879 |x 1946-6242 |7 nnns |
| 773 | 1 | 8 | |g volume:16 |g year:2024 |g number:732 |g day:31 |g month:01 |g pages:eadg6229 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1126/scitranslmed.adg6229 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 16 |j 2024 |e 732 |b 31 |c 01 |h eadg6229 | ||