Epigenetic Modification of the von Willebrand Factor Promoter Drives Platelet Aggregation on the Pulmonary Endothelium in Chronic Thromboembolic Pulmonary Hypertension.

Abstract

Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.

• Authors: Xue D Manz, Robert Szulcek, Xiaoke Pan, Petr Symersky, Chris Dickhoff, Jisca Majolée, Veerle Kremer, Elisabetta Michielon, Ekaterina S Jordanova, Teodora Radonic, Irene V Bijnsdorp, Sander R Piersma, Thang V Pham, Connie R Jimenez, Anton Vonk Noordegraaf, Frances S de Man, Reinier A Boon, Jan Voorberg, Peter L Hordijk, Jurjan Aman, Harm Jan Bogaard
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 205 Issue 7 Pg. 806-818 (04 01 2022) ISSN: 1535-4970 [Electronic] United States
• PMID: 35081007 (Publication Type: Journal Article)

Chemical References

• von Willebrand Factor

Topics

• Endothelial Cells (metabolism)
• Endothelium, Vascular
• Epigenesis, Genetic
• Humans
• Hypertension, Pulmonary
• Platelet Aggregation
• Proteomics
• von Willebrand Factor (analysis, genetics, metabolism)