Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation

Abstract

Objective: Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell–derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells ( Fstl1 ECKO ) led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice with Fstl1 knockout in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers of Fstl1 ECKO mutants. The SMAD3 (mothers against decapentaplegic homolog 3) phosphorylation (pSMAD3) was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells of Fstl1 ECKO mice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels in Fstl1 ECKO mutant mice. Conclusions: The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.

Key Proteins for Regeneration inA. mexicanum: Transcriptomic Insights from Aged and Juvenile Limbs

“…FSTL1 has been found to be critical for tracheal and central nervous system development in mice, with Fstl1 -/- mice exhibiting cyanotic traits due to tracheal malformations (Geng et al, 2011; Yang et al, 2009). It is also involved in vascularization and vascular epithelial homeostasis maintenance (Jiang et al, 2020; Ouchi et al, 2008). Overall, the observed downregulation of ADAMTS17 and FSTL1 in aged axolotls compared to juvenile limbs further highlights the importance of the extracellular environment during limb regeneration.…”

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats

“…Fstl1 is a secreted glycoprotein that is reportedly cardioprotective ( Tanaka et al, 2016 ). Deletion of this gene results in excessive smooth muscle actin associated with atrial endocardia, heart valves, veins and micro-vessels through SMAD3 activation, but also collagen deposits in the atria ( Jiang et al, 2020 ). Serum levels of Fstl1 are elevated in human patients with pulmonary hypertension related to COPD, and in the lungs of hypoxic mice with high right ventricular systolic pressure (RVSP) and RVH ( Zhang et al, 2017 ).…”

FSTL1-USP10-Notch1 Signaling Axis Protects Against Cardiac Dysfunction Through Inhibition of Myocardial Fibrosis in Diabetic Mice

“…If there has a therapeutic strategy that can balance this pathological change? Previous studies have suggested that FSTL1 attenuated pathological injury of multiple organs by alleviating fibrosis, particularly in cardiac dysfunction ( Jiang et al, 2020 ; Hu et al, 2020 ; Li et al, 2021 ; Z.; Chen Z. et al, 2019 ; Yang et al, 2020 ). Our current findings are consistent with these aforementioned research findings that the upregulation of FSTL1 in DM compared with the control group, which was further increased in T2DM with MI.…”

“…Previous studies reported a protective role of FSTL1 in doxorubicin-induced cardiotoxicity through upregulation of Nrf2 to suppress apoptosis and oxidative stress ( Zhao et al, 2020 ). FSTL1 insufficiency leads to venous wall and atrial fibrosis by switching on SMAD3 signaling ( Jiang et al, 2020 ). Further, Wei et al applied an epicardial patch with human FSTL1 protein to rescue cardiac dysfunction in swine and mouse MI models through inhibition of myocardial fibrosis ( Wei et al, 2015 ; Shen et al, 2019 ; Hu et al, 2020 ; Xi et al, 2020 ).…”