The HIF‐1α pathway plays a critical role in salivary gland development in ex vivo organ cultures

• Published in: FEBS open bio Vol. 12; no. 2; pp. 460 - 469
• Main Authors: Kimura, Tomomasa, Sakai, Manabu, Gojo, Nao, Watanabe, Mikio, Uzawa, Narikazu, Sakai, Takayoshi
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2022; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Apoptosis; Autophagy; Cell cycle; Cell growth; Cell proliferation; Dentistry; development; Embryos; Erythropoietin; Exocrine glands; Female; Gene expression; Glucose; Glucose transporter; HIF‐1α; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-like growth factors; Laboratories; Medical research; Mice; Mice, Inbred ICR; Morphogenesis; Morphology; Organ Culture Techniques; Salivary gland; salivary glands; Salivary Glands - metabolism; Signal transduction; Submandibular gland; Transcription factors; Variance analysis; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; United States > US; Japan; hypoxia; salivary glands; development; HIF-1α
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.13351

The transcription factor, hypoxia‐inducible factor‐1α (HIF‐1α), has previously been shown to upregulate the expression of hypoxia‐related genes, including erythropoietin (EPO). However, the role of hypoxia‐inducible factor‐1α in morphogenesis during salivary gland development is unclear. We investigated the function of HIF‐1α in submandibular gland (SMG) organ cultures obtained from embryonic day 13.5 embryos from ICR female mice. Expression of HIF‐1α, glucose transporter 1, and vascular endothelial growth factor was induced under hypoxia (5% O2). We further showed that BAY 87‐2243‐mediated inhibition of HIF‐1α suppressed salivary gland development. Under severe hypoxia (1% O2), HIF‐1α did not promote salivary gland development; this was due to suppression of cell proliferation and inhibition of the cell cycle and not because of autophagy and apoptosis. Additionally, using the inhibitor U0126, we verified that the ERK1/2 pathway is upstream of HIF‐1α. Overall, we found that the HIF‐1α signaling pathway plays a critical role in salivary gland development in ex vivo SMG organ cultures. The role of the HIF‐1α signaling pathway in salivary gland development is currently unknown. Through the use of inhibitors, including U0126 and BAY87‐2243, we demonstrated that the HIF‐1α signaling pathway, including phosphorylated ERK and HIF‐1α signaling pathway‐related proteins (VEGF and GLUT1), plays a critical role in salivary gland development in ex vivo organ culture.