The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension

• Published in: Vascular pharmacology 2024-06, Vol.155, p.107379, Article 107379
• Main Authors: Schlueter, Beate Christiane, Quanz, Karin, Baldauf, Julia, Petrovic, Aleksandar, Ruppert, Clemens, Guenther, Andreas, Gall, Henning, Tello, Khodr, Grimminger, Friedrich, Ghofrani, Hossein-Ardeschir, Weissmann, Norbert, Seeger, Werner, Schermuly, Ralph Theo, Weiss, Astrid
• Format: Article
• Language: English
• Subjects: Adult; Animals; Case-Control Studies; Cells, Cultured; Disease Models, Animal; ErbB Receptors - metabolism; Familial Primary Pulmonary Hypertension - genetics; Familial Primary Pulmonary Hypertension - metabolism; Familial Primary Pulmonary Hypertension - pathology; Familial Primary Pulmonary Hypertension - physiopathology; Female; Humans; Hypoxia; IGF-1 signaling; IGF1R knock-down; IGFBP inhibition; Insulin-Like Growth Factor Binding Protein 1 - genetics; Insulin-Like Growth Factor Binding Protein 1 - metabolism; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor binding proteins; Insulin-Like Growth Factor I - metabolism; Male; Mice, Inbred C57BL; Middle Aged; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Peptide-based kinase activity assay; Phosphorylation; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary Artery - physiopathology; Pulmonary hypertension; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Signal Transduction; STAT3 Transcription Factor - metabolism; Vascular Remodeling
• ISSN: 1537-1891; 1879-3649; 1879-3649
• DOI: 10.1016/j.vph.2024.107379

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. [Display omitted]