Endothelin-1 driven proliferation of PASMC is c-fos dependent

Background: Pulmonary hypertension is a rare disease characterized by pulmonary artery smooth muscle cell (PASMC) proliferation leading to vascularremodeling. Multiple factors have been associated with the vessel wall thickening. However, the responsible mechanisms are not fully understood. Aim: In this study we aim to decipher the role ofc-fos and c-jun transcription factors in the vascular remodeling process. Methods and Results: Expression and immunohistochemical analyses revealed high expression of c-fos and c-jun transcription factors in the vessel wall of lungs from human IPAH samples, hypoxia exposed mice and monocrotaline treated rats. Microarray study from hypoxic lung homogenates revealed MAP kinase asthe most differentially regulated pathway. Additionally, ET-1 and CTGF were the most up-regulated genes. Consequently, ET-1 but not CTGF stimulation of human PASMCs increased DNA synthesis and expression of proliferative markers such as Ki67 and cell cycle regulator, cyclin D1. Moreover, ET-1 treatment elevated ERK-dependent c-fos expression and phosphorylation of c-fos and c-jun. Silencing of c-fos with siRNA abrogated the ET-1-induced proliferation of PASMC. Conclusion: This finding shed light on the involvement of c-fos/c-jun in vascular remodeling as well as on the molecular mechanisms regulating the proliferative response of PASMCs to ET-1. 36 mice were divided into 2 groups and kept either under normoxic (Nox) or under hypoxic conditions (Hox.3h). RNA from 3 animals was pooled to get 6 pools per group. Each pool was subjected to microarray hybridization (Nox vs. Hox.3h) in a balanced dye-swap design, giving a total of 6 dual-color hybridizations.