Follistatin-like 1 is crucial for normal postnatal development of the pulmonary vasculature

    Tania, Navessa P. MSc | Department of Molecular Pharmacology University of Groningen | 23 augustus 2016 | (

In chronic lung diseases, e.g. chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH) is a common comorbidity. PAH is a progressive disease that is characterized by vascular remodeling and sustained vasoconstriction which consequently leads to high blood pressure in the pulmonary vasculature and right ventricle remodeling (1). Altered bone morphogenetic protein (BMP) signaling, including aberrant activation of SMAD1/5/8, has been implicated in the pathogenesis of PAH (2). Endothelial dysfunction and alterations in embryonic development of pulmonary vasculature may contribute to PAH development (3). The BMP antagonist Follistatin-like 1 (Fstl1) is highly expressed in the pulmonary vascular endothelium of the developing murine lung, suggesting its involvement in pulmonary vasculature, in addition to its known crucial role in lung morphogenesis (4–6).

At the Experimental Biology (EB) 2016, I presented our data at the angiogenesis in organ development and function session, demonstrating that the conditional knockdown of Fstl1 from endothelium (Fstl1 cKO) is postnatally lethal and results in activation of BMP-mediated protein expression and microvasculature remodeling, presumably due to increased vasoconstrictor endothelin-1 expression (7). During normal postnatal development, Fstl1 mRNA expression in lung tissue was higher at 1 week compared to 3 weeks after birth. In line with the idea that Fstl1 is a BMP inhibitor, BMP signaling was more active at 3 weeks than 1 week after birth, reflected by the higher level of phosphorylated Smad1/5/8. Moreover, the mRNA levels of the BMP/Smad-regulated genes JAG1 and endothelin-1 were significantly increased 3 weeks after birth compared to 1 week. In the Fstl1 cKO mice, Fstl1 mRNA expression was significantly reduced compared to wildtype mice at 1 week, whereas at 3 weeks, Fstl1 mRNA expression was unaltered in Fstl1 cKO compared to wildtype mice. Endothelial deletion of Fstl1 resulted in activation of BMP/Smad signaling and increased BMP/Smad-regulated gene expression, including JAG1, endoglin, and endothelin-1 at 1 week. At 3 weeks, JAG1 was reduced whereas endoglin and endothelin-1 were unchanged. Moreover, the percentage of actin-positive small pulmonary vessels was increased at 3 weeks old of Fstl1 cKO mice compared to wildtype mice whereas it was unaltered at 1 week. Our data suggested that the loss of endothelial deletion of Fstl1 results in dysregulation of BMP/Smad-mediated gene expression and could contribute to microvascular remodeling (7).

Hypoxia is an important factor in the development of PAH. It has been suggested that vasoconstriction may contribute to chronic hypoxia-induced PAH. At EB 2016, Sheak and colleagues presented data suggesting that chronic hypoxia contributes to spontaneous increased in pulmonary microvascular pressure via PKCβ and reactive oxygen species (ROS) signaling in rat neonates (8). Furthermore, it has been demonstrated that hypoxia elevates NF-κβ in the lung. A poster presented by Kang and colleagues suggested that targeting PPARγ using rosiglitazone inhibits hypoxia-induced NF-κβ activation and decreases microRNA-98 levels in the lung, by increasing E3 ubiquitin ligase expression thereby promoting ubiquitylation of NF-κβ and termination of its downstream signaling (9). These studies provide a possible molecular mechanism of hypoxia induced PAH and activating PPARγ might be a potential therapeutic intervention to inhibit hypoxia-induced NF-κβ signaling in PAH.

In addition to our study, there was a poster presented by Chiou and colleagues demonstrated that Fstl1 has protective roles in lung adenocarcinoma by inhibiting tumor growth and metastatic behavior of cancer cells colleagues (10). They demonstrated that low levels of Fstl1 correlate with poor prognosis of lung cancer. Fstl1 expression is downregulated in lung cancer and is negatively correlated with the migratory ability of lung cancer cell lines in vitro. Recombinant Fstl1 protein inhibits migration and invasion of highly metastatic lung cancer CL1-5 cell line in a dose-dependent manner. In contrast, the migratory capacity of poorly metastatic lung cancer CL1-0 cell line is dose-dependently enhanced by blocking Fstl1. Furthermore, the overexpression of Fstl1 suppressed metastatic potential of CL1-5 and CL1-0 lung cancer cell lines. Accordingly, the knockdown of Fstl1 promotes metastatic potential of CL1-5 and CL1-0 lung cancer cell lines (10). These results suggest that the administration of Fstl1 could be a potential therapeutic strategy to inhibit tumor metastasis in lung adenocarcinoma.

Unraveling the role of BMP signaling in normal lung morphogenesis, pulmonary vasculature, and injury-repair processes is needed in order to identify a potential drug target and develop a rational targeted therapy to improve the treatment of pulmonary vascular diseases, chronic lung diseases and lung cancer. Attending EB international conference is not solely to present and discuss our current findings with the experts in the field, but also worthwhile to keep up to date to current understanding and exchange ideas with leading scientists. Furthermore, it is a great opportunity to build scientific networks and start up collaboration with other scientists.

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7. Tania NP, Maarsingh H, Bos ST, Mattiotti A, Prakash S, Timens W, et al. Endothelial Follistatin-like 1 Regulates The Maturation of The Pulmonary Vasculature by Modulating BMP/Smad Signaling. FASEB J. 2016 Apr 1;30(1 Supplement):300.1-300.1.
8. Sheak JR, Jernigan NL, Walker BR, Resta TC. Chronic Hypoxia Elevates Basal Tone in Neonatal Pulmonary Hypertension through PKCβ and Reactive Oxygen Species Signaling. FASEB J. 2016 Apr 1;30(1 Supplement):774.16-774.16.
9. Kang B-Y, Kleinhenz JM, Murphy TC, Sutliff RL, Hart CM. Hypoxia Reduces HUWE1 by Downregulating PPARγ in Mouse Lungs and Human Pulmonary Artery Endothelial Cells. FASEB J. 2016 Apr 1;30(1 Supplement):774.13-774.13.
10. Chiou J, Su C-Y, Lin Y-F, Hsiao M. FSTL1 Inhibits Tumor Growth and Metastatic Progression via Blocking Proteolytic Activation of SPP1 in Lung Adenocarcinoma. FASEB J. 2016 Apr 1;30(1 Supplement):699.1-699.1.


Keyword: COPD comorbidity Follistatin-like 1 pulmonary vasculature

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