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15 August 2017 : Laboratory Research  

Metastasis-Associated Protein 1 Deficiency Results in Compromised Pulmonary Alveolar Capillary Angiogenesis in Mice

Jun-Hui Qin1BCDE, Zhen-Yu Ke1C, Qiang Zhou2C, Li Wang1B, Yuan Liang1B, Ying-Mei Wang1F, Tong Yang1B, Xing Gao1F, Jing Ye1A, Rekesh Kumar34C, Rui-An Wang15G*

DOI: 10.12659/MSM.905992

Med Sci Monit 2017; 23:3932-3941

Abstract

BACKGROUND: The aim of this study was to investigate the effects of metastasis-associated protein 1 (MTA1) deficiency during angiogenesis of pulmonary alveolar capillaries in mice and to determine the molecular mechanisms involved.

MATERIAL AND METHODS: The expressions of MTA1, CD34, vascular endothelial growth factor (VEGF), alpha smooth muscle actin (α-SMA), and HIF-1α were analyzed in the lungs of MTA1-knockout (KO) and wild-type mice at embryonic day 18.5 and 2 months by quantitative PCR, immunoblotting, and immunohistochemistry. The morphological changes were investigated during pulmonary alveolar capillary formation. The heart weight/body weight (HW/BW) ratio and the size of the right ventricular wall cardiomyocytes were also measured. Regulation of MTA1 on HIF-1α was determined in vitro.

RESULTS: MTA1 deficiency reduced the number of pulmonary alveolar capillaries compared to the wild-type mice. MTA1-KO mice exhibited a decreased expression of HIF-1α and VEGF in the lungs. The retarded growth of the MTA1-KO mice was also noticed during the first week after birth. Accordingly, MTA1 deficiency resulted in increased infant mortality. In surviving adult mice, MTA1 deficiency induced myocardial hypertrophy, highlighted by an increased heart weight/body weight ratio and larger cardiomyocytes. In cultured cells, HIF-1α and VEGF levels were significantly upregulated upon MTA1 overexpression, suggesting a close relationship between all 3 molecules.

CONCLUSIONS: MTA1 participates in the formation of pulmonary capillaries via stabilization of HIF-1α. This finding sheds new light on the function of MTA1 in lung development, opening new avenues for the diagnosis/treatment of related pulmonary diseases.

Keywords: Mice, Knockout, Neovascularization, Physiologic, Persistent Fetal Circulation Syndrome

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750