Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

Amit Prabhakar; Rahul Kumar; Meetu Wadhwa; Prajakta Ghatpande; Jingkun Zhang; Ziwen Zhao; Carlos O Lizama; Bhushan N Kharbikar; Stefan Gräf; Carmen M Treacy; Nicholas W Morrell; Brian B Graham; Giorgio Lagna; Akiko Hata

doi:10.1038/s44161-024-00495-z

Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response

Nat Cardiovasc Res. 2024 Jul;3(7):799-818. doi: 10.1038/s44161-024-00495-z. Epub 2024 Jul 9.

Authors

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
² Lung Biology Center, Pulmonary and Critical Care Medicine, Zuckerberg San Francisco General Hospital, San Francisco, CA, USA.
³ Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Medicine, University of Cambridge, Cambridge, UK.
⁶ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. [email protected].
⁷ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA. [email protected].

^# Contributed equally.

PMID: 39196173
PMCID: PMC11409862 (available on 2025-05-09)
DOI: 10.1038/s44161-024-00495-z

Abstract

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.

MeSH terms

Animals
Antigens, CD / genetics
Antigens, CD / metabolism
Bone Morphogenetic Protein Receptors, Type II* / genetics
Bone Morphogenetic Protein Receptors, Type II* / metabolism
Cadherins / genetics
Cadherins / metabolism
Capillary Permeability / drug effects
Disease Models, Animal*
Humans
Male
Mutation
Phenotype*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pulmonary Veno-Occlusive Disease* / drug therapy
Pulmonary Veno-Occlusive Disease* / genetics
Pulmonary Veno-Occlusive Disease* / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects
Vascular Remodeling / drug effects

Substances

Bone Morphogenetic Protein Receptors, Type II
Cadherins
Antigens, CD
cadherin 5
BMPR2 protein, human
Protein Kinase Inhibitors

Abstract

MeSH terms

Substances

Grants and funding