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

Prabhakar, A.; Kumar, R.; Wadhwa, M.; Ghatpande, P.; Zhang, J.; Zhao, Z.; Lizama, C. O.; Kharbikar, B. N.; Graf, S.; Treacy, C. M.; Morrell, N. W.; Graham, B. B.; Lagna, G.; Hata, A.

doi:10.1101/2023.11.27.568924

bioRxiv · 10.1101/2023.11.27.568924

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

Prabhakar, A.·Kumar, R.·Wadhwa, M.·Ghatpande, P.·Zhang, J.·Zhao, Z.·Lizama, C. O.·Kharbikar, B. N.·Graf, S.·Treacy, C. M.·Morrell, N. W.·Graham, B. B.·Lagna, G.·Hata, A.

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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 the vascular remodeling in PVOD. We show that the administration of MMC in rats mediates the activation of protein kinase R (PKR) and the integrated stress response (ISR), which lead to the release of the endothelial adhesion molecule VE-Cadherin in the complex with Rad51 to the circulation, disruption of endothelial barrier, and vascular remodeling. Pharmacological inhibition of PKR or ISR attenuates the depletion of VE-Cadherin, 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 BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD.

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Prabhakar, A., Kumar, R., Wadhwa, M., Ghatpande, P., Zhang, J., Zhao, Z., Lizama, C. O., Kharbikar, B. N., Graf, S., Treacy, C. M., Morrell, N. W., Graham, B. B., Lagna, G., Hata, A.. 2023-11-28. Reversal of pulmonary veno-occlusive disease phenotypes by inhibition of the integrated stress response. https://doi.org/10.1101/2023.11.27.568924

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