The diverging roles of insulin-like growth factor binding proteins in pulmonary arterial hypertension.
Vascul Pharmacol
; 155: 107379, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38762131
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arteria Pulmonar
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Factor I del Crecimiento Similar a la Insulina
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Transducción de Señal
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Receptor IGF Tipo 1
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Proteína 1 de Unión a Factor de Crecimiento Similar a la Insulina
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Proteína 2 de Unión a Factor de Crecimiento Similar a la Insulina
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Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina
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Miocitos del Músculo Liso
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Modelos Animales de Enfermedad
Idioma:
En
Revista:
Vascul Pharmacol
Asunto de la revista:
ANGIOLOGIA
/
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article