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Effect of Intermittent Hypobaric Hypoxia Exposure on HIF-1α, VEGF, and Angiogenesis in the Healing Process of Post-Tooth Extraction Sockets in Rats
Objective The aim of this study was to investigate the effect of intermittent hypobaric hypoxia (IHH) exposure on the expression of hypoxia-induced factor-1α (HIF-1α) messenger RNA (mRNA), vascular endothelial growth factor-a (VEGF-a) mRNA, and angiogenesis after tooth extraction in rats.
Materials and Methods On 45 male Sprague-Dawley rats were performed the removal of the maxillary left first molar, and then they were randomly divided into 9 groups, namely: 4 groups that were exposed to IHH for 30 minutes every day in the Hypobaric Chamber at an altitude of 18,000 feet, with 1 time hypobaric hypoxia (HH), 3 times HH, 5 times HH, and 7 times HH; 4 normoxia groups that were terminated on days 1, 3, 5, and 7 after tooth extraction; and the 1 control group. Real-time polymerase chain reaction measured the molecular changes in the socket tissue after tooth extraction in rats to evaluate the expression of HIF-1α mRNA and VEGF mRNA. Histological changes with hematoxylin and eosin staining were noted to evaluate the amount of angiogenesis in the socket after tooth extraction. Molecular and histological parameters were calculated at the end of each experiment on days 0, 1, 3, 5, and 7 after tooth extraction, which exhibited the improvement phase of the wound-healing process.
Results Increases in the expression of HIF-1α mRNA, VEGF mRNA, and angiogenesis were found in the IHH group compared with the normoxia group and the control group. The expression of HIF-1α mRNA increased significantly (p < 0.05) in the group after one time HH exposure on day 1, then decreased in the IHH group (three times HH exposure, five times HH exposure, and seven times HH exposure) approaching the control group. The expression of VEGF mRNA and angiogenesis began to increase after one time HH exposure on day 1, and increased again after three times HH exposure on day 3, then increased even more after five times HH exposure on day 5, and increased very significantly (**p < 0.05) after seven times HH exposure on day 7. It showed that repeated or intermittent exposure to HH conditions induced a protective response that made cells adapt under hypoxia conditions.
Conclusion IHH exposure accelerates the socket healing of post-tooth extraction, which is proven by changes in HIF-1α mRNA expression and increase in VEGF mRNA expression as stimuli for angiogenesis in post-tooth extraction sockets under hypobaric hypoxic condition, which also stimulates the formation of new blood vessels, thereby increasing blood supply and accelerating wound healing.
All authors were involved in primary data collection, analysis, documentation of collection, and publication of the writing.
Received: 27 March 2023
Accepted: 29 March 2023
Article published online:
09 June 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
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- 1 Politis C, Schoenaers J, Jacobs R, Agbaje JO. Wound healing problems in the mouth. Front Physiol 2016; 7: 507
- 2 Pagni G, Pellegrini G, Giannobile WV, Rasperini G. Postextraction alveolar ridge preservation: biological basis and treatments. Int J Dent 2012; 2012: 151030
- 3 Cohen N, Cohen-Lévy J. Healing processes following tooth extraction in orthodontic cases. J Dentofac Anomalies Orthod 2014; 17: 304
- 4 de Sousa Gomes P, Daugela P, Poskevicius L, Mariano L, Fernandes MH. Molecular and cellular aspects of socket healing in the absence and presence of graft materials and autologous platelet concentrates: a focused review. J Oral Maxillofac Res 2019; 10 (03) e2
- 5 Guo S, Dipietro LA. Factors affecting wound healing. J Dent Res 2010; 89 (03) 219-229
- 6 Gilany K, Vafakhah M. Hypoxia: a review. J Paramed Sci 2010; 1 (01) 43-60
- 7 Hong WX, Hu MS, Esquivel M. et al. The role of hypoxia-inducible factor in wound healing. Adv Wound Care (New Rochelle) 2014; 3 (05) 390-399
- 8 D'Alessandro S, Magnavacca A, Perego F. et al. Effect of hypoxia on gene expression in cell populations involved in wound healing. BioMed Res Int 2019; 2019: 2626374
- 9 Kumar Singh LCS. Spectrum of oral diseases in high altitude area & its association with cardiovascular risk factors. J Med Sci Clin Res 2019; 7 (04) 69
- 10 Alam P, Saini N, Pasha MA. MicroRNAs: an apparent switch for high-altitude pulmonary edema. MicroRNA 2015; 4 (03) 158-167
- 11 Ahmad Y, Sharma NK, Ahmad MF, Sharma M, Garg I, Bhargava K. Proteomic identification of novel differentiation plasma protein markers in hypobaric hypoxia-induced rat model. PLoS One 2014; 9 (05) e98027
- 12 Tarver WJ, Volner K, Cooper JS. Aerospace Pressure Effects. 2017
- 13 Davis JR, Johnson R, Stepanek J, Fogarty JA. Fundamentals of Aerospace Medicine: Fourth Edition. Wolters Kluwer Health Adis (ESP); 2011: 724
- 14 Hinkelbein J, Jansen S, Iovino I. et al. Thirty minutes of hypobaric hypoxia provokes alterations of immune response, haemostasis, and metabolism proteins in human serum. Int J Mol Sci 2017; 18 (09) 1882
- 15 Mulyani SWM, Astuti ER, Wahyuni OR, Ernawati DS, Ramadhani NF. Xerostomia therapy due to ionized radiation using preconditioned bone marrow-derived mesenchymal stem cells. Eur J Dent 2019; 13 (02) 238-242
- 16 Coimbra-Costa D, Garzón F, Alva N. et al. Intermittent hypobaric hypoxic preconditioning provides neuroprotection by increasing antioxidant activity, erythropoietin expression and preventing apoptosis and astrogliosis in the brain of adult rats exposed to acute severe hypoxia. Int J Mol Sci 2021; 22 (10) 5272
- 17 Herawati M, Wardaya, Mulyawan W. et al. Expression of hypoxia-inducible factor-1α and myoglobin in rat heart as adaptive response to intermittent hypobaric hypoxia exposure. Hayati J Biosci 2017; 24: 131-135
- 18 Dewi S, Yulhasri Y, Mulyawan W. The impact of intermittent hypobaric hypoxia exposures on triacylglycerol synthesis in rat liver. Rep Biochem Mol Biol 2021; 10 (03) 437-444
- 19 Khoswanto C. A new technique for research on wound healing through extraction of mandibular lower incisors in Wistar rats. Eur J Dent 2019; 13 (02) 235-237
- 20 Mabesau. Petunjuk Teknis Indoktrinasi Dan Latihan Aerofisiologis (ILA) Bagi Awak Pesawat. Keputusan Kepala Staf Angkatan Udara Nomor Kep/267/X/2020.; 2020
- 21 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Δ Δ C(T)) method. Methods 2001; 25 (04) 402-408
- 22 Viscor G, Torrella JR, Corral L. et al. Physiological and biological responses to short-term intermittent hypobaric hypoxia exposure: from sports and mountain medicine to new biomedical applications. Front Physiol 2018; 9: 814
- 23 Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007; 2007 (407) cm8
- 24 Kumar H, Choi DK. Hypoxia inducible factor pathway and physiological adaptation: a cell survival pathway?. Mediators Inflamm 2015; 2015: 584758
- 25 Frede S, Berchner-Pfannschmidt U, Fandrey J. Regulation of hypoxia-inducible factors during inflammation. Methods Enzymol 2007; 435: 405-419
- 26 Guo D, Wang Q, Li C, Wang Y, Chen X. VEGF stimulated the angiogenesis by promoting the mitochondrial functions. Oncotarget 2017; 8 (44) 77020-77027
- 27 Schipani E, Maes C, Carmeliet G, Semenza GL. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res 2009; 24 (08) 1347-1353
- 28 Melincovici CS, Boşca AB, Şuşman S. et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018; 59 (02) 455-467
- 29 Nirwana I, Rachmadi P, Rianti D. Potential of pomegranate fruit extract (Punica granatum Linn.) to increase vascular endothelial growth factor and platelet-derived growth factor expressions on the post-tooth extraction wound of Cavia cobaya . Vet World 2017; 10 (08) 999-1003
- 30 Morelli T, Neiva R, Nevins ML. et al. Angiogenic biomarkers and healing of living cellular constructs. J Dent Res 2011; 90 (04) 456-462
- 31 Lim HC, Thoma DS, Jeon M, Song JS, Lee SK, Jung UW. Effect of hypoxia-inducible factor 1α on early healing in extraction sockets. BioMed Res Int 2018; 2018: 8210637