Abstract
Pulmonary hypertension (PH) remains a life-limiting disease characterized by pulmonary vascular remodelling due to aberrant proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), thus leading to raised pulmonary arterial pressure and right ventricular hypertrophy. Secreted glycoprotein follistatin-like 1 (FSTL1) has been reported to ameliorate tissue remodelling in cardiovascular injuries. However, the role of FSTL1 in deranged pulmonary arteries remains elusive. We found that there were higher serum levels of FSTL1 in patients with PH related to chronic obstructive pulmonary diseases (COPD) and in mice model of hypoxia-induced PH (HPH). Haploinsufficiency of Fstl1 in mice contributed to an exacerbated HPH, as demonstrated by increased right ventricular systolic pressure, pulmonary arterial muscularization and right ventricular hypertrophy index. Conversely, FSTL1 administration attenuated HPH. In cultured human PASMCs, hypoxia-promoted cellular viability, DNA synthesis and migration were suppressed by exogenous FSTL1 but enhanced by small interfering RNA targeting FSTL1. Additionally, FSTL1 inhibited the proliferation and migration of PASMCs via extracellular regulated kinase (ERK) signal pathway. All these findings indicate that FSTL1 imposed a protective modulation on pulmonary vascular remodelling, thereby suggesting its role in the regulation of HPH.
Highlights
We setup a hypoxia mouse model of Pulmonary hypertension (PH) and measured the substantially elevated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) by week 2 and week 4, respectively, after hypoxia exposure (Fig. 1b and c, P < 0.01 for both RVSP and RVHI compared to untreated mice)
The role of FSTL1 on hypoxia-induced PH (HPH) was suggested by the increased RVSP and pulmonary arterial remodelling in hypoxia-treated Fstl1+/− mice relative to their wide type (WT) littermates, with enhanced extracellular regulated kinase (ERK) phosphorylation and disrupted AMPK activity in lung tissue
We demonstrated that systemic delivery of FSTL1 protein at least partly under hypoxia
Summary
Based on its extracellular calcium-binding and follistatin-like domains, FSTL1 belongs to the secreted protein acidic and rich in cysteine (SPARC) family. This family has been appreciated to play a critical role in organogenesis and human disease pathogenesis[19]. FSTL1 could preserve the viability of ECs and SMCs both in vivo and in vitro[15,16,21,26] In pulmonary circulation, it is highly expressed in blood vessels of the developing lung[27], but its role in stressful arteries, such as in HPH, is not elucidated. Our finding suggested a protective role of FSTL1 in pulmonary vascular remodelling, pointing to its potential clinical value for patients with HPH
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
