Angiocrine FSTL1 insufficiency leads to atrial and vein wall fibrosis via SMAD3 activation
Ralf H. Adams,
Posted 23 Apr 2019
bioRxiv DOI: 10.1101/616623
Posted 23 Apr 2019
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. Here we show that loss of follistatin-like protein 1 (FSTL1) in endothelial cells (Fstl1ECKO) 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 deletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive alpha-smooth muscle actin (αSMA) associated with atrial endocardia, heart valves, veins and microvessels after the endothelial FSTL1 deletion. Consistently, there was an increase of collagen deposition as demonstrated in livers of Fstl1ECKO mutants. The SMAD3 phosphorylation was significantly enhanced and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ signaling in vascular mural cells of Fstl1ECKO mice. The findings imply that endothelial FSTL1 is critical for the homeostasis of atria and veins and its insufficiency may favor cardiovascular fibrosis leading to heart failure.
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