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Follistatin-like 1 (Fstl1) is a secreted glycoprotein which is highly expressed during development and disease , including cardiac disease and cancer. In the early mouse embryo Fstl1 is broadly expressed but with ongoing development, its expression pattern becomes restricted to mesenchymal cells. A detailed analysis of the available commercial antisera directed against Fstl1 was performed, allowing the detailed analysis of the expression pattern of Fstl1 during mouse cardiac development and disease. After a myocardial infarction (MI), Fstl1 is highly and transiently expressed in the damaged area, especially in activated and proliferative fibroblasts involved in the scar formation. Deletion of Fstl1 from proliferating fibroblasts in the forming scar, results in cardiac rupture within one week after surgery due to impaired scar formation. Studying the transcriptional regulation of Fstl1 expression, two hypoxia responsive elements were identified, of which one was shown to be TGF-β responsive. Testing these regulatory elements in vivo showed that these sequences drive the transient expression of the reporter in the infarct area after the induction of an MI, which closely resembles the endogenous Fstl1 expression. In an attempt to discover pathogenic mutations in the Fstl1 gene, over 50 patients with cardiac and skeletal defects resembling the Fstl1 knock-out phenotype were screened. Two novel variants were identified in regions that might regulate gene expression. Taking together, our data shows the cardioprotective role of Fstl1 during myocardial infarction and provides new insights for developing novel therapies.

Pulmonary arterial hypertension (PAH) is a progressive disease that is characterized by vascular remodeling and sustained vasoconstriction which consequently lead to high blood pressure in the pulmonary vasculature and right ventricle remodeling. Altered bone morphogenetic protein (BMP) signaling has been implicated in the pathogenesis of PAH as well as in pulmonary vascular maturation. The endogenous BMP antagonist follistatin-like 1 (Fstl1) is highly expressed in pulmonary vascular endothelium of the developing lung in mice, suggesting a role in pulmonary vessel formation. In this study, the role of Fstl1 in the maturation of the pulmonary vasculature was investigated using Tie2-cre mediated endothelial-specific Fstl1 knockout mice. To this end, Fstl1fl/flmice were bred with Fstl1WT/KO Tie2-cremice to generate Fstl1KO/fl Tie2-cremice and control littermates Fstl1WT/fl Tie2-cre, Fstl1KO/fl, and Fstl1WT/fl. Heart and lung tissue was collected from pups at 1 and 3 weeks after birth. The percentage of actin-positive small vessels per total number of vessels was determined. The expression level of Fstl1 and BMP/Smad-regulated genes was determined in total RNA isolated from lungs using qPCR. Activation of BMP signaling was investigated using western blot. In wildtype mice, the mRNA expression of Fstl1 was higher in lung tissue at 1 week than 3 weeks (p