Endothelial periostin regulates vascular remodeling by promoting endothelial dysfunction in pulmonary arterial hypertension

Anim Cells Syst (Seoul). 2024 Jan 3;28(1):1-14. doi: 10.1080/19768354.2023.2300437. eCollection 2024.

Abstract

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling associated with extracellular matrix (ECM) deposition, vascular cell hyperproliferation, and neointima formation in the small pulmonary artery. Endothelial dysfunction is considered a key feature in the initiation of vascular remodeling. Although vasodilators have been used for the treatment of PAH, it remains a life-threatening disease. Therefore, it is necessary to identify novel therapeutic targets for PAH treatment. Periostin (POSTN) is a secretory ECM protein involved in physiological and pathological processes, such as tissue remodeling, cell adhesion, migration, and proliferation. Although POSTN has been proposed as a potential target for PAH treatment, its role in endothelial cells has not been fully elucidated. Here, we demonstrated that POSTN upregulation correlates with PAH by analyzing a public microarray conducted on the lung tissues of patients with PAH and biological experimental results from in vivo and in vitro models. Moreover, POSTN overexpression leads to ECM deposition and endothelial abnormalities such as migration. We found that PAH-associated endothelial dysfunction is mediated at least in part by the interaction between POSTN and integrin-linked protein kinase (ILK), followed by activation of nuclear factor-κB signaling. Silencing POSTN or ILK decreases PAH-related stimuli-induced ECM accumulation and attenuates endothelial abnormalities. In conclusion, our study suggests that POSTN serves as a critical regulator of PAH by regulating vascular remodeling, and targeting its role as a potential therapeutic strategy for PAH.

Keywords: Pulmonary arterial hypertension; endothelial cell; extracellular matrix; periostin.

Grants and funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), the Ministry of Education (NRF-2020R1I1A1A01071987, NRF-RS-2023-00248674 to A.L. and NRF-RS-2023-00207857, NRF-2022R1A2C1003866 to J.K).