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

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 heterozygousBMPR2mutation that truncates the carboxyl tail of BMPR2, underscoring the role of deregulated BMP signal in the development of PVOD.

Depletion of Protein Phosphatase 1 Results in Persistent Activation of the Integrated Stress Response and Age-Associated Exacerbation of Pulmonary Veno-Occlusive Disease

“…Pharmacologically, the administration of chemotherapeutic agents, such as mitomycin C (MMC), bleomycin, and cisplatin, has been implicated in the onset of PVOD (5)(6)(7). Specifically, MMC administration to rats induces a spectrum of PVOD-like phenotypes, including right ventricular (RV) hypertrophy and changes in the pulmonary vasculature, including medial thickening and obstruction of the lumen in PAs and PVs, fibrous growth in the intima and adventitia, and thrombosis (6,(8)(9)(10)(11).…”

“…VE-Cad is a critical component of the adherens junctions (AJs) in endothelial cells, playing an essential role in maintaining permeability and vascular integrity (12). Previous studies have demonstrated that VE-Cad localizes at the AJs in complex with Rad51 (hereafter referred to as VE-Cad:Rad51 complex or VRC) (11). The interaction between Rad51 and VE-Cad is essential for the stability of VE-Cad, as well as for preserving the integrity of endothelial cell-cell junctions and barrier function (11).…”

“…Previous studies have demonstrated that VE-Cad localizes at the AJs in complex with Rad51 (hereafter referred to as VE-Cad:Rad51 complex or VRC) (11). The interaction between Rad51 and VE-Cad is essential for the stability of VE-Cad, as well as for preserving the integrity of endothelial cell-cell junctions and barrier function (11). MMC treatment leads to the depletion of VE-Cad and Rad51 in endothelial cells partially through the ubiquitin-proteasomedependent degradation of Rad51, which results in the destabilization of VE-Cad (11).…”

“…The interaction between Rad51 and VE-Cad is essential for the stability of VE-Cad, as well as for preserving the integrity of endothelial cell-cell junctions and barrier function (11). MMC treatment leads to the depletion of VE-Cad and Rad51 in endothelial cells partially through the ubiquitin-proteasomedependent degradation of Rad51, which results in the destabilization of VE-Cad (11). Additionally, MMC treatment contributes to VE-Cad depletion by promoting the release of the VRC from endothelial cells into the extracellular space (11).…”

“…MMC treatment leads to the depletion of VE-Cad and Rad51 in endothelial cells partially through the ubiquitin-proteasomedependent degradation of Rad51, which results in the destabilization of VE-Cad (11). Additionally, MMC treatment contributes to VE-Cad depletion by promoting the release of the VRC from endothelial cells into the extracellular space (11). Inhibiting Rad51 degradation by silencing of the E3 ubiquitin ligase for Rad51 Fbh1 or excess amount of Rad51 in the cell protects VE-Cad after MMC treatment and maintains the barrier function (11).…”