Endothelial Follistatin-Like 1 Regulates The Maturation Of The Pulmonary Vasculature By Modulating Bmp/Smad Signaling

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