Journal article

Publication year: 2024

Journal: Vascular Pharmacology

Volume number: 155

ISSN: 1537-1891

eISSN: 1879-3649

Open access status: Hybrid

DOI Link: https://doi.org/10.1016/j.vph.2024.107379

Publisher: Elsevier

Abstract: 
Pulmonary hypertension (PH) is a progressive, severe and to date not curable disease of the pulmonary vasculature. Alterations of the insulin-like growth factor 1 (IGF-1) system are known to play a role in vascular pathologies and IGF-binding proteins (IGFBPs) are important regulators of the bioavailability and function of IGFs. In this study, we show that circulating plasma levels of IGFBP-1, IGFBP-2 and IGFBP-3 are increased in idiopathic pulmonary arterial hypertension (IPAH) patients compared to healthy individuals. These binding proteins inhibit the IGF-1 induced IGF-1 receptor (IGF1R) phosphorylation and exhibit diverging effects on the IGF-1 induced signaling pathways in human pulmonary arterial cells (i.e. healthy as well as IPAH-hPASMCs, and healthy hPAECs). Furthermore, IGFBPs are differentially expressed in an experimental mouse model of PH. In hypoxic mouse lungs, IGFBP-1 mRNA expression is decreased whereas the mRNA for IGFBP-2 is increased. In contrast to IGFBP-1, IGFBP-2 shows vaso-constrictive properties in the murine pulmonary vasculature. Our analyses show that IGFBP-1 and IGFBP-2 exhibit diverging effects on IGF-1 signaling and display a unique IGF1R-independent kinase activation pattern in human pulmonary arterial smooth muscle cells (hPASMCs), which represent a major contributor of PAH pathobiology. Furthermore, we could show that IGFBP-2, in contrast to IGFBP-1, induces epidermal growth factor receptor (EGFR) signaling, Stat-3 activation and expression of Stat-3 target genes. Based on our results, we conclude that the IGFBP family, especially IGFBP-1, IGFBP-2 and IGFBP-3, are deregulated in PAH, that they affect IGF signaling and thereby regulate the cellular phenotype in PH.

Harvard Citation style: Schlueter, B., Quanz, K., Baldauf, J., Petrovic, A., Ruppert, C., Guenther, A., et al. (2024) The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension, Vascular Pharmacology, 155, Article 107379. https://doi.org/10.1016/j.vph.2024.107379

APA Citation style: Schlueter, B., Quanz, K., Baldauf, J., Petrovic, A., Ruppert, C., Guenther, A., Gall, H., Tello, K., Grimminger, F., Ghofrani, H., Weissmann, N., Seeger, W., Schermuly, R., & Weiss, A. (2024). The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension. Vascular Pharmacology. 155, Article 107379. https://doi.org/10.1016/j.vph.2024.107379