Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response.
Animals
Pulmonary Veno-Occlusive Disease
/ genetics
Bone Morphogenetic Protein Receptors, Type II
/ genetics
Phenotype
Disease Models, Animal
Vascular Remodeling
/ drug effects
Cadherins
/ genetics
Humans
Male
Antigens, CD
/ metabolism
Rats, Sprague-Dawley
Signal Transduction
/ drug effects
Mutation
Capillary Permeability
/ drug effects
Rats
Protein Kinase Inhibitors
/ pharmacology
Journal
Nature cardiovascular research
ISSN: 2731-0590
Titre abrégé: Nat Cardiovasc Res
Pays: England
ID NLM: 9918284280206676
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
received:
24
03
2023
accepted:
29
05
2024
medline:
28
8
2024
pubmed:
28
8
2024
entrez:
28
8
2024
Statut:
ppublish
Résumé
Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension arising from EIF2AK4 gene mutations or mitomycin C (MMC) administration. The lack of effective PVOD therapies is compounded by a limited understanding of the mechanisms driving vascular remodeling in PVOD. Here we show that administration of MMC in rats mediates activation of protein kinase R (PKR) and the integrated stress response (ISR), which leads to the release of the endothelial adhesion molecule vascular endothelial (VE) cadherin (VE-Cad) in complex with RAD51 to the circulation, disruption of endothelial barrier and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates VE-Cad depletion, elevation of vascular permeability and vascular remodeling instigated by MMC, suggesting potential clinical intervention for PVOD. Finally, the severity of PVOD phenotypes was increased by a heterozygous BMPR2 mutation that truncates the carboxyl tail of the receptor BMPR2, underscoring the role of deregulated bone morphogenetic protein signaling in the development of PVOD.
Identifiants
pubmed: 39196173
doi: 10.1038/s44161-024-00495-z
pii: 10.1038/s44161-024-00495-z
doi:
Substances chimiques
Bone Morphogenetic Protein Receptors, Type II
EC 2.7.11.30
Cadherins
0
Antigens, CD
0
cadherin 5
0
BMPR2 protein, human
EC 2.7.11.30
Protein Kinase Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
799-818Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL132058
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL153915
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL164581
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : R01HL135872
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : P01HL152961
Organisme : Tobacco-Related Disease Research Program (TRDRP)
ID : 28IR-0047
Organisme : American Heart Association (American Heart Association, Inc.)
ID : 19CDA34730030
Organisme : British Heart Foundation (BHF)
ID : RG/19/3/34265
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Limited.
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