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2022, Vol. 26 ›› Issue (17): 2708-2712Calcium-sensitive receptors influence pulmonary vascular remodeling in neonatal mice with persistent pulmonary hypertensionZhu Yaping1, Li Xiang1, Chen Zhiwen1, Liu Ying1, Zhao Wenzhuo1, Ma Ketao2, Gu Qiang1
Abstract: BACKGROUND: Previous studies have shown the up-regulated expression of calcium-sensitive receptors in the neonatal mouse model of persistent pulmonary hypertension. The up-regulation trend is more obvious in the calcium-sensitive receptor agonist group, while the expression is declined somewhat in the calcium-sensitive receptor inhibitor group. OBJECTIVE: To explore the mechanism of calcium-sensitive receptors in pulmonary remodeling in neonatal mice with hypoxia-induced persistent pulmonary hypertension. METHODS: Eighty newborn C57BL/6 mice were randomly divided into four groups. Mice in the hypoxic group, the hypoxic+agonist group (hereinafter referred to as agonist group), and the hypoxic+antagonist group (hereinafter referred to as antagonist group) were placed in a hypoxic chamber simultaneously (oxygen concentration 12%). In addition, the agonist and antagonist groups were given intraperitoneal injection of calcium-sensitive receptor agonist GdCl3 (16 mg/kg) and inhibitor NPS2390 (1 mg/kg) once a day respectively. Mice in the normoxia group were exposed to air and injected with the same amount of normal saline daily as that in the hypoxic group. After 14 days, heart and lung tissues were removed. The thickness of ventricular wall and pulmonary vascular wall was measured and alveolar morphology was observed. The level of B-type brain natriuretic peptide was determined by enzyme linked immunosorbent assay. Western blot and immunohistochemistry were used to detect the expression and localization of caveolin-1 protein in mouse lung tissue, and qRT-PCR was used to detect the expression of caveolin-1 mRNA. The study protocol was approved by the Experimental Animal Ethic Committee of the First Affiliated Hospital of Shihezi University School of Medicine (approval No. 2018-172-01). RESULTS AND CONCLUSION: After 14 days of hypoxia, the wall thickness of small pulmonary arterioles in mice increased, and the thickness ratio of right ventricle to left ventricle and B-type brain natriuretic peptide level increased in the hypoxic group compared with the normoxia group. The average alveolar lining interval was widened and the radial alveolar count decreased in the hypoxic group compared with the normoxia group. Western blot and qRT-PCR results showed that the expression levels of caveolin-1 protein and mRNA were up-regulated hypoxic group compared with the normoxia group (P < 0.05). These changes were more significant in the agonist group (P < 0.05), while the inhibitor group reversed the changes caused by hypoxia (P < 0.05). To conclude, calcium-sensitive receptor affects the vascular remodeling in the lung of neonatal mice with persistent pulmonary hypertension, and the mechanism may be related to the changes in the caveolin-1 expression. Key words: caveolin-1, calcium-sensitive receptor, vascular remodeling, persistent pulmonary hypertension, mouse |