Absence of the MFG-E8 gene prevents hypoxia-induced pulmonary hypertension in mice.

Abstract

Pulmonary hypertension (PH) is a chronic vascular disease characterized by elevated pulmonary arterial resistance and vascular remodeling, and chronic hypoxia plays an important role in PH. Milk fat globule‐EGF factor 8 (MFG‐E8) is a glycoprotein that regulates cell proliferation and apoptosis, but its role in hypoxia‐induced PH is unknown. The current study aimed to determine the function and fundamental mechanisms of MFG‐E8 in hypoxia‐induced PH. Herein, we exposed mice to hypoxia for 5 weeks, and MFG‐E8 was found to be elevated in mouse lung tissues, arteries, and plasma. Compared with wild‐type littermates, mice lacking MFG‐E8 showed a significant increase in the ratio of pulmonary artery acceleration time to ejection time (PAT/PET), while they showed decreases in right ventricular systolic pressure, the Fulton's Index, percent medial wall thickness (%WT), and vascular muscularization in pulmonary arteries. In addition, MFG‐E8 protein levels were also increased in the serum of patients with chronic PH. Similarly, we observed a higher expression of MFG‐E8 in human pulmonary artery smooth muscle cells (PASMCs) in the presence of hypoxic stimulation than MFG‐E8 in cells in normoxic conditions. Furthermore, MFG‐E8 silencing resulted in partial inhibition of proliferation, migration and cell cycle progression in human PASMCs, and the possible mechanisms might involve the interaction between MFG‐E8 and the p‐Akt/cyclin D1 pathway. Collectively, our study suggests that the absence of MFG‐E8 can attenuate the development of hypoxia‐induced PH and vascular remodeling. MFG‐E8 can be a potential therapeutic target or a biomarker for PH.