Author(s):
Ista Damayanti, Wawan Mulyawan, Bambang Pontjo Priosoeryanto, Meirina Gartika, Harmas Yazid Yusuf
Email(s):
istadamayanti79@gmail.com
DOI:
10.52711/0974-360X.2025.00201 
Address:
Ista Damayanti1*, Wawan Mulyawan2, Bambang Pontjo Priosoeryanto3, Meirina Gartika4, Harmas Yazid Yusuf5
1Study of Program of Military Dentistry, Faculty of Dentistry, Universitas Padjadjaran, Bandung, Jawa Barat, Indonesia.
2Department of Community Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
3Department of Veterinary Clinic Reproduction and Pathology, Faculty of Veterinary, Universitas Pertanian Bogor, Bogor, Indonesia.
4Department of Pediatric Dentistry, Faculty of Dentistry, Padjadjaran University, Bandung, Jawa Barat, Indonesia.
5Department of Oral Maxillofacial Surgery, Faculty of Dentistry, PadjadjaranUniversity, Bandung, Jawa Barat, Indonesia.
*Corresponding Author
Published In:
Volume - 18,
Issue - 3,
Year - 2025
ABSTRACT:
This scoping review aims to investigate the impact of Intermittent Hypobaric Hypoxia (IHH) Therapy on the immune expression of Hypoxia-Inducible Factor-1 alpha (HIF-1a) and Vascular Endothelial Growth Factor (VEGF) in the context of osteogenesis of the mandibular bone. Through a systematic literature search of the PubMed, Scopus, and Web of Science databases, this review assessed the evidence linking IHH to increased expression of HIF-1a and VEGF, which play essential roles in osteogenesis and angiogenesis. Several studies showed that IHH exposure significantly increased the expression of HIF-1a and VEGF, which contributed to the stimulation of osteogenesis and angiogenesis in the mandibular bone, as seen from the histological and radiographic parameters improvement. The conclusions of this review support the concept that IHH can facilitate osteogenesis of the mandibular bone through mechanisms involving activation of HIF-1a and increased expression of VEGF.
Cite this article:
Ista Damayanti, Wawan Mulyawan, Bambang Pontjo Priosoeryanto, Meirina Gartika, Harmas Yazid Yusuf. Impact of Intermittent Hypobaric Hypoxia on HIF-1α and VEGF Expression for Mandibular Bone Osteogenesis: A Scoping Review. Research Journal of Pharmacy and Technology. 2025;18(3):1394-4. doi: 10.52711/0974-360X.2025.00201
Cite(Electronic):
Ista Damayanti, Wawan Mulyawan, Bambang Pontjo Priosoeryanto, Meirina Gartika, Harmas Yazid Yusuf. Impact of Intermittent Hypobaric Hypoxia on HIF-1α and VEGF Expression for Mandibular Bone Osteogenesis: A Scoping Review. Research Journal of Pharmacy and Technology. 2025;18(3):1394-4. doi: 10.52711/0974-360X.2025.00201 Available on: https://rjptonline.org/AbstractView.aspx?PID=2025-18-3-62
REFERENCES:
1. Suciadi SP, Nugraha AP, Ernawati DS, et al. The efficacy of human dental pulp stem cells in regenerating submandibular gland defects in diabetic wistar rats (Rattus novergicus). Research Journal of Pharmacy and Technology. 2019; 12(4): 1573-79. https://doi.org/10.5958/0974-360X.2019.00261.0
2. Arviana SD, Yueniwati Y, Rahayu M, Syaban MFR. 7, 8-dihydroxyflavone as a neuroprotective agent in ischemic stroke through the regulation of HIF-1α protein. Research Journal of Pharmacy and Technology. 2022; 15(9): 3980-86. https://doi.org/10.52711/0974-360X.2022.00667
3. Herrera Videla E, Farías J, González Candia A, et al. Omega3 Supplementation and Intermittent Hypobaric Hypoxia Induce Cardioprotection Enhancing Antioxidant Mechanisms in Adult Rats. 2015. https://doi.org/10.3390/md13020838
4. Li X, Zhang J, Liu G, et al. High altitude hypoxia and oxidative stress: The new hope brought by free radical scavengers. Life Sciences. 2023: 122319. https://doi.org/10.1016/j.lfs.2023.122319
5. Qin Q, Liu Y, Yang Z, et al. Hypoxia-inducible factors signaling in osteogenesis and skeletal repair. International Journal of Molecular Sciences. 2022; 23(19): 11201. https://doi.org/10.3390/ijms231911201
6. Bahtiar MRH, Anwar AA, Farhana FAE, Prameswari S, Munadziroh E. An insight of Osthole, Bone marrow mesenchymal stem cells, and BMP-9 loaded carbon-based scaffolds as a Biomaterial candidate in Osteoporosis Therapy: A Narrative Review. Research Journal of Pharmacy and Technology. 2023; 16(1): 459-64. https://doi.org/10.52711/0974-360X.2023.00078
7. Rao U, Yusoff HBM. Unraveling the association of tobacco smoking (nicotine) with gut and adipocyte appetite regulator hormones-A systematic review. Research Journal of Pharmacy and Technology. 2019; 12(2): 913-19. https://doi.org/10.5958/0974-360X.2019.00156.2
8. Usategui-Martín R, Rigual R, Ruiz-Mambrilla M, et al. Molecular mechanisms involved in hypoxia-induced alterations in bone remodeling. International Journal of Molecular Sciences. 2022; 23(6): 3233. https://doi.org/10.3390%2Fijms23063233
9. Patyar S. Role of Stem Cells in treatment of different Diseases. Research Journal of Pharmacy and Technology. 2018; 11(8): 3667-78. https://doi.org/10.5958/0974-360X.2018.00674.1
10. Percival CJ, Richtsmeier JT. Angiogenesis and intramembranous osteogenesis. Developmental Dynamics. 2013; 242(8): 909-22. https://doi.org/10.1002/dvdy.23992
11. Hartmann C, Yang Y. Molecular and cellular regulation of intramembranous and endochondral bone formation during embryogenesis. Principles of Bone Biology: Elsevier; 2020; 5-44. http://dx.doi.org/10.1016/B978-0-12-814841-9.00001-4
12. Chan WCW, Tan Z, To MKT, Chan D. Regulation and role of transcription factors in osteogenesis. International Journal of Molecular Sciences. 2021; 22(11): 5445. https://doi.org/10.3390/ijms22115445
13. Fadhil SAN, Mubarak HJ. A Morphometric Evaluation of the Humerus in relation to Shoulder Arthroplasty. Research Journal of Pharmacy and Technology. 2020; 13(10): 4817-22. https://doi.org/10.5958/0974-360X.2020.00847.1
14. Besio R, Chow CW, Tonelli F, Marini JC, Forlino A. Bone biology: insights from osteogenesis imperfecta and related rare fragility syndromes. Febs J. 2019; 286(15): 3033-56. https://doi.org/10.1111/febs.14963
15. Dalfino S, Savadori P, Piazzoni M, et al. Regeneration of Critical‐Sized Mandibular Defects Using 3D‐Printed Composite Scaffolds: A Quantitative Evaluation of New Bone Formation in In Vivo Studies. Advanced Healthcare Materials. 2023; 12(21): 2300128. https://doi.org/10.1002/adhm.202300128
16. Xue N, Ding X, Huang R, et al. Bone Tissue Engineering in the Treatment of Bone Defects. Pharmaceuticals (Basel). 2022; 15(7). https://doi.org/10.3390%2Fph15070879
17. Yang YQ, Tan YY, Wong R, et al. The role of vascular endothelial growth factor in ossification. Int J Oral Sci. 2012; 4(2): 64-8. https://doi.org/10.1038/ijos.2012.33
18. Thompson EM, Matsiko A, Farrell E, Kelly DJ, O'Brien FJ. Recapitulating endochondral ossification: a promising route to in vivo bone regeneration. Journal of Tissue Engineering and Regenerative Medicine. 2015; 9(8): 889-902.https://doi.org/10.1002/term.1918
19. Aswin SK, Jothishwar S, Nayagam P, Priya G. Scaffolds for biomolecule delivery and controlled release-A Review. Research Journal of Pharmacy and Technology. 2018; 11(10): 4719-30. https://doi.org/10.5958/0974-360X.2018.00861.2
20. Mendoza SV, Genetos DC, Yellowley CE. Hypoxia Inducible Factor 2α Signaling in the Skeletal System. Journal of Bone and Mineral Research Plus. 2023; 7(4): e10733. https://doi.org/10.1002%2Fjbm4.10733
21. Chen P, Liu Y, Liu W, et al. Impact of High-Altitude Hypoxia on Bone Defect Repair: A Review of Molecular Mechanisms and Therapeutic Implications. Frontiers in Medicine. 2022; 9. https://doi.org/10.3389%2Ffmed.2022.842800
22. Setiawan K, Setyaningsih A, Sari DN, et al. The Therapeutic Potentials of Intermittent Hypoxia on Bone Healing: A Systematic Review. Journal of International Dental and Medical Research. 2022; 15(4): 1838-44.
23. Wahyuningsih SPA, Atika BND, Sajidah ES, Winarni D. Nephroprotective activity of okra pods extract (Abelmoschus esculentus L.) in sodium nitrite-induced mice. Research Journal of Pharmacy and Technology. 2020; 13(8): 3648-52. https://doi.org/10.5958/0974-360X.2020.00645.9
24. Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacology and Therapeutics. 2016; 164: 152-69. https://doi.org/10.1016/j.pharmthera.2016.04.009
25. Herrera EA, Farías JG, González-Candia A, et al. Ω3 Supplementation and Intermittent Hypobaric Hypoxia Induce Cardioprotection Enhancing Antioxidant Mechanisms in Adult Rats. Marine Drugs. 2015; 13(2): 838-60. https://doi.org/10.3390%2Fmd13020838
26. Mélou C, Pellen-Mussi P, Jeanne S, et al. Osteoarthritis of the Temporomandibular Joint: A Narrative Overview. Medicina (Kaunas). 2022; 59(1). https://doi.org/10.3390%2Fmedicina59010008
27. Camacho-Cardenosa M, Camacho-Cardenosa A, Timón R, et al. Can Hypoxic Conditioning Improve Bone Metabolism? A Systematic Review. International Journal of Environmental Research and Public Health. 2019; 16(10): 1799. https://doi.org/10.3390%2Fijerph16101799
28. Arvidson K, Abdallah BM, Applegate LA, et al. Bone regeneration and stem cells. J Cell Mol Med. 2011; 15(4): 718-46. https://doi.org/10.1111/j.1582-4934.2010.01224.x
29. Zhang L, Jin L, Hou Z. Chronic intermittent hypobaric hypoxia. enhances bone fracture healing. Frontiers in Endocrinology 2021; 11: 582670. https://doi.org/10.3389%2Ffendo.2020.582670
30. Lekvijittada K, Hosomichi J, Maeda H, et al. Intermittent hypoxia inhibits mandibular cartilage growth with reduced TGF-β and SOX9 expressions in neonatal rats. Sci Rep. 2021; 11(1): 1140. https://www.nature.com/articles/s41598-020-80303-3
31. Fan L, Li J, Yu Z, Dang X, Wang K. The Hypoxia-Inducible Factor Pathway, Prolyl Hydroxylase Domain Protein Inhibitors, and Their Roles in Bone Repair and Regeneration. BioMed Research International. 2014; 2014: 239356. https://doi.org/10.1155/2014/239356
32. Sun X, Wei Y. The role of hypoxia-inducible factor in osteogenesis and chondrogenesis. Cytotherapy. 2009; 11(3): 261-67. https://doi.org/10.1080/14653240902824765
33. Mayr-Wohlfart U, Waltenberger J, Hausser H, et al. Vascular endothelial growth factor stimulates chemotactic migration of primary human osteoblasts. Bone. 2002; 30: 472-7. https://doi.org/10.1016/s8756-3282(01)00690-1
34. Amin MN, Permatasari N. The role of stem cell on orthodontic tooth movement induced-alveolar bone remodeling. Research Journal of Pharmacy and Technology. 2023; 16(1): 123-28. https://doi.org/10.52711/0974-360X.2023.00023
35. Brent MB. A review of the skeletal effects of exposure to high altitude and potential mechanisms for hypobaric hypoxia-induced bone loss. Bone. 2022; 154: 116258. https://doi.org/10.1016/j.bone.2021.116258
36. Chen G, Deng C, Li Y-P. TGF-β and BMP signaling in osteoblast differentiation and bone formation. International Journal of Biological Sciences. 2012; 8(2): 272. https://doi.org/10.7150/ijbs.2929
37. Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignancy and ischemia. Yale J Biol Med. 2007; 80(2): 51-60. http://www.ncbi.nlm.nih.gov/pmc/articles/pmc2140184/
38. Thomas LW, Ashcroft M. Exploring the molecular interface between hypoxia-inducible factor signalling and mitochondria. Cellular and Molecular Life Sciences. 2019; 76(9): 1759-77. https://doi.org/10.1007/s00018-019-03039-y
39. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol 2003; 23(24): 9361-74. https://doi.org/10.1128/mcb.23.24.9361-9374.2003
40. Schipani E, Maes C, Carmeliet G, Semenza GL. Regulation of osteogenesis-angiogenesis coupling by HIFs and VEGF. J Bone Miner Res. 2009; 24(8): 1347-53. https://doi.org/10.1359/jbmr.090602
41. 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(2): 455-67.
42. Huang X, Zhao L, Peng R. Hypoxia-inducible factor 1 and mitochondria: an intimate connection. Biomolecules. 2022; 13(1): 50. https://doi.org/10.3390%2Fbiom13010050
43. Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nature reviews Molecular cell Biology. 2016; 17(10): 611-25. https://doi.org/10.1038/nrm.2016.87
44. Hu K, Olsen BR. The roles of vascular endothelial growth factor in bone repair and regeneration. Bone. 2016; 91: 30-8. https://doi.org/10.1016/j.bone.2016.06.013
45. Tirpe AA, Gulei D, Ciortea SM, Crivii C, Berindan-Neagoe I. Hypoxia: overview on hypoxia-mediated mechanisms with a focus on the role of HIF genes. International Journal of Molecular Sciences. 2019; 20(24): 6140. https://doi.org/10.3390/ijms20246140
46. Chen W, Wu P, Yu F, et al. HIF-1α Regulates Bone Homeostasis and Angiogenesis, Participating in the Occurrence of Bone Metabolic Diseases. Cells. 2022; 11(22). https://doi.org/10.3390/cells11223552
47. Uccelli A, Wolff T, Valente P, et al. Vascular endothelial growth factor biology for regenerative angiogenesis. Swiss Medical Weekly. 2019; 149(0304): w20011-w11. https://doi.org/10.4414/smw.2019.20011
48. Falcon BL, Chintharlapalli S, Uhlik MT, Pytowski B. Antagonist antibodies to vascular endothelial growth factor receptor 2 (VEGFR-2) as anti-angiogenic agents. Pharmacology and Therapeutics. 2016; 164: 204-25. https://doi.org/10.1016/j.pharmthera.2016.06.001
49. Beamer B, Hettrich C, Lane J. Vascular Endothelial Growth Factor: An Essential Component of Angiogenesis and Fracture Healing. HSS Journal. 2010; 6(1): 85-94. https://doi.org/10.1007%2Fs11420-009-9129-4
50. Befani C, Liakos P. The role of hypoxia‐inducible factor‐2 alpha in angiogenesis. Journal of Cellular Physiology. 2018; 233(12): 9087-98.https://doi.org/10.1002/jcp.26805
51. Szade A, Grochot‐Przeczek A, Florczyk U, Jozkowicz A, Dulak J. Cellular and molecular mechanisms of inflammation‐induced angiogenesis. IUBMB Life 2015; 67(3): 145-59.https://doi.org/10.1002/iub.1358
52. Johnson T, Zhao L, Manuel G, Taylor H, Liu D. Approaches to therapeutic angiogenesis for ischemic heart disease. Journal of Molecular Medicine. 2019; 97: 141-51. https://doi.org/10.1007/s00109-018-1729-3
53. Di Martino E, Rayasam A, Vexler ZS. Brain maturation as a fundamental factor in immune-neurovascular interactions in stroke. Translational Stroke Research. 2024; 15(1): 69-86. https://doi.org/10.1007/s12975-022-01111-7
54. Zimna A, Kurpisz M. Hypoxia-inducible factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. BioMed Research International. 2015; 2015. https://doi.org/10.1155/2015/549412
55. Fialho MdLS, Abd Jamil AH, Stannard GA, Heather LC. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2019; 1865(4): 831-43. https://doi.org/10.1016/j.bbadis.2018.09.024
56. Wan C, Gilbert SR, Wang Y, et al. Activation of the hypoxia-inducible factor-1α pathway accelerates bone regeneration. Proceedings of the National Academy of Sciences. 2008; 105(2): 686-91. https://doi.org/10.1073/pnas.0708474105
57. Emami Nejad A, Najafgholian S, Rostami A, et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment. Cancer Cell International. 2021; 21: 1-26. https://doi.org/10.1186/s12935-020-01719-5
58. Batmomolin A, Khotimah H, Ahsan A, Wiyasa I, Santoso S. Effects of quercetin and kaempferol (Main Compound of Moringa oleifera leaves) improve IUGR through decreased hypoxia. Research Journal of Pharmacy and Technology. 2020; 13(12): 5831-36. http://dx.doi.org/10.5958/0974-360X.2020.01016.1
59. Burtscher M, Millet GP, Burtscher J. Hypoxia conditioning for high-altitude pre-acclimatization. Journal of Science in Sport and Exercise. 2022: 1-15. http://dx.doi.org/10.1007/s42978-021-00150-0
60. Kaplan JM, Sharma N, Dikdan S. Hypoxia-Inducible Factor and Its Role in the Management of Anemia in Chronic Kidney Disease. Int J Mol Sci. 2018; 19(2). https://doi.org/10.3390/ijms19020389
61. Kumar H, Choi D-K. Hypoxia inducible factor pathway and physiological adaptation: a cell survival pathway? Mediators of Inflammation. 2015; 2015. https://doi.org/10.1155/2015/584758
62. Lv X, Li J, Zhang C, et al. The role of hypoxia-inducible factors in tumor angiogenesis and cell metabolism. Genes and Diseases. 2017; 4(1): 19-24. https://doi.org/10.1016%2Fj.gendis.2016.11.003
63. Zhang W, Yang F, Yan Q, et al. Hypoxia inducible factor-1α related mechanism and TCM intervention in process of early fracture healing. Chinese Herbal Medicines. 2024; 16(1): 56-69. https://doi.org/10.1016%2Fj.chmed.2023.09.006
64. Jin F, Zheng X, Yang Y, et al. Impairment of hypoxia-induced angiogenesis by LDL involves a HIF-centered signaling network linking inflammatory TNFα and Angiogenic VEGF. Aging (Albany NY) 2019; 11(2): 328. https://doi.org/10.18632/aging.101726
65. Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor--HIF-1α in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem. 2012; 19(1): 90-7. https://doi.org/10.2174/092986712803413944
66. Lucero García Rojas EY, Villanueva C, Bond RA. Hypoxia inducible factors as central players in the pathogenesis and pathophysiology of cardiovascular diseases. Frontiers in Cardiovascular Medicine. 2021; 8: 709509. https://doi.org/10.3389/fcvm.2021.709509
67. You J, Liu M, Li M, et al. The Role of HIF-1α in Bone Regeneration: A New Direction and Challenge in Bone Tissue Engineering. Int J Mol Sci. 2023; 24(9). https://doi.org/10.3390/ijms24098029