Cannabidiol as a possible treatment for endometriosis through suppression of inflammation and angiogenesis
Department of Obstetrics and Gynecology, Hamadan University of Medical Sciences, Hamadan, Iran
School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
Abstract
Background
Endometriosis is associated with a wide variety of signs and symptoms and can lead to infertility, embryo death, and even miscarriage. Although the exact pathogenesis and etiology of endometriosis is still unclear, it has been shown that it has a chronic inflammatory nature and angiogenesis is also involved in it.
Objective
This review aims to explore the role of inflammation and angiogenesis in endometriosis and suggest a potential treatment targeting these pathways.
Findings
Among the pro‐inflammatory cytokines, studies have shown solid roles for interleukin 1β (IL‐β), IL‐6, and tumor necrosis factor α (TNF‐α) in the pathogenesis of this condition. Other than inflammation, angiogenesis, the formation of new blood vessels from pre‐existing capillaries, is also involved in the pathogenesis of endometriosis. Among angiogenic factors, vascular endothelial growth factor (VEGF), hypoxia‐inducible factor 1α (HIF‐1α), transforming growth factor β1 (TGF‐β1), and matrix metalloproteinases (MMPs) are more essential in the pathogenesis of endometriosis. Interestingly, it has been shown that inflammation and angiogenesis share some similar pathways with each other that could be potentially targeted for treatment of diseases caused by these two processes. Cannabidiol (CBD) is a non‐psychoactive member of cannabinoids which has well‐known and notable anti‐inflammatory and antiangiogenic properties. This agent has been shown to decrease IL‐1β, IL‐6, TNF‐α, VEGF, TGFβ, and MMPs in different animal models of diseases.
Conclusion
It seems that CBD could be a possible treatment for endometriosis due to its anti‐inflammatory and antiangiogenic activity, however, further studies are needed.
Untitled section
Keywords: angiogenesis, cannabidiol, cannabinoids, endometriosis, inflammation
Graphical
Endometriosis is a chronic disease in which inflammation and angiogenesis are involved in it. Cannabidiol is an anti‐inflammatory and antiangiogenic agent derived from Cannabis sativa. It seems that cannabidiol could be an effective treatment for endometriosis through inhibition of inflammation and angiogenesis.
Boxed Text
Article notes
Untitled section
Revised 2024 Jul 8; Received 2023 Sep 26; Accepted 2024 Jul 26; Collection date 2024 Aug.
1.INTRODUCTION
Reports estimate the endometriosis prevalence to be 10%–15% in the general female population of reproductive age. 1 This pathology is associated with dysmenorrhea, dyspareunia, dyschezia, and dysuria. 2 Clinically, endometriosis could increase the risk of infertility, 3 embryo death, and even miscarriage. 4 Considering the mentioned outcomes, this condition strongly affects life quality and socioeconomically condition of those affected. 5 Endometriosis is recognized by the existence of functional endometrial glands as well as stroma in exterior side of the uterine cavity in a chronic setting. 1 Among the common sites of presence, ovaries, the uterosacral ligaments, the fossa ovarica, and the posterior cul‐de‐sac are more prevalent than the others. 1 In some aspects, endometriosis is comparable with malignancies as they both tend to be recurrent, invasive, metastatic, and have estrogen‐dependent growth. 6 , 7 Although the exact etiology and mechanism of endometriosis is still unknown, retrograde menstruation is seriously suspected. However, other causes/etiologies such as immune system abnormalities, genetics and environmental issues, and coelomic metaplasia have been considered as well. It has been suggested that it's possible for at least two of the mentioned causes to be involved together. 2 This article aims to review the role of inflammation and angiogenesis in the endometriosis and suggest a new possible treatment candidate for research: cannabidiol (CBD).
2.SEARCH STRATEGY
For this study, different databases such as PubMed, Scopus, and ISI Web of Science were searched from the inception to Jun 2023 with keywords including “Endometriosis; Angiogenesis; Inflammation; Cannabinoids; Cannabidiol.” Only English studies were included and different types of studies such as in vitro, ex vivo, in vivo, and clinical trials were used for data extraction.
2.1.Endometriosis and inflammation
Endometriosis is considered as a chronic inflammatory condition. 4 The pro‐inflammatory cytokines such as interleukin 1β (IL‐β), IL‐6, and tumor necrosis factor α (TNF‐α) not only increase the inflammation but also are involved in the adhesion of endometrial tissue to the peritoneal surface. Also, they could increase production of metalloproteinases (MMPs) which leads to shedding of the endometrial tissue fragments. 8
IL‐1β is a pro‐inflammatory cytokine from interleukin‐1 family which gets activated in the inflammasome to exert a wide range of inflammatory action. 9 As it has been shown, levels of proIL‐1β and IL‐1β in the peritoneal fluid of women with endometriosis were significantly higher than controls. 10 , 11 As we showed before, the serum levels of IL‐1β were significantly higher in patients with endometrioma compared to healthy controls. 12 Also, the levels of this pro‐inflammatory cytokine have been shown to be associated with the dyspareunia in the women with endometriosis. 13
Inflammasomes are multi‐protein structures involved in both innate and adaptive immune system responses. They are involved in the production of different ILs such as IL1β. Aside from their IL production roles, inflammasomes are also key role players of endometriosis and, therefore, potent treatment targets. 14 According to the investigations, estrogen receptor‐β (ERβ) is greatly increased in the endometriosis compared to normal endometrial tissues. It has been shown that ERβ of endometrial cells interacts with “cell death machinery” to prevent the TNF‐α‐induced apoptosis. Also, it increases IL‐1β production through an inflammasome‐mediated pathway to boost the cellular proliferation. Among the inflammasomes that ERβ interacts with in the endometriotic tissues are NOD‐, LRR, caspase I, and pyrin domain‐containing 3 (NLRP3) which all are involved in IL‐1β production pathway. 15
IL‐6, an acute phase reactant, is a very crucial cytokine in inflammation and immune response. 16 According to the results of our previous study, IL‐6 levels (serum) were significantly higher in patients with endometrioma compared to healthy controls. 12 It has been shown that the expression of this cytokine was increased in the endometriotic tissues compared to the normal endometrial cells. Also, treatment of the mentioned cells with IL‐1β led to a dramatic increase in IL‐6 expression. 17 Moreover, it has been shown that the expression of IL‐6 and soluble IL‐6 in plasma and peritoneal fluid was significantly higher in endometriotic patients compared to the controls. 18 Also, there are other studies implicating the involvement of IL‐6 in the pathogenesis of endometriosis. 19 , 20
TNF‐α is a potent inflammatory cytokine of the TNF superfamily with a notable role in inflammation. 21 This inflammatory cytokine has been shown to be involved in the pathogenesis of endometriosis. 4 According to the investigations, TNF‐α is upregulated in the endometrial tissues of patients with endometriosis compared to normal endometrial tissues which supports the role of inflammation in this disorder. 2 Also, the level of IL‐16 is found to be increased in the peritoneal fluid of cases diagnosed with endometriosis. This in turn suggests a possible involved pathway in the inflammatory process of this disorder. 22 Not only IL‐16, but also IL‐8 and Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES or CCL5) are increased in peritoneal fluid of women with endometriosis. 11 , 23 Moreover, peritoneal fluid analysis in the early stage endometriosis has revealed the increased levels of IL‐12. 24
2.2.Endometriosis and angiogenesis
Angiogenesis is defined as new blood vessel formation from the pre‐existing capillaries. This process is observed in a few physiological conditions including female reproductive cycle 25 and wound healing. 26 On the other hand, angiogenesis participates in the pathogenesis of solid tumors growth, 27 corneal neovascularization, 28 hemophilic arthropathy, 29 psoriasis, 30 and endometriosis. 31 Also, endometriosis is associated with a chronic inflammatory response 4 that could cause endothelial dysfunction. 32 Same as the tumors, angiogenesis and “dense vascularization” has been known as a characteristic condition in endometriosis for which antiangiogenesis therapies have been suggested in different studies. 31 , 33 , 34
An increased unmet demand for oxygen leading to hypoxia could cause overexpression of hypoxia‐inducible factor 1α (HIF‐1α) which in turn could activate certain downstream pathways. The expression of HIF‐1α has been demonstrated to be significantly increased in ectopic endometriotic lesions compared to the controls. 35 , 36 Also, vascular endothelial growth factor (VEGF) and HIF‐1α are both proven to be overexpressed in the endometrial tissues with ectopic location. 36 , 37 In cases with ovarian endometriosis, an increased expression of HIF‐1α and nitric oxide synthase isoforms has been detected. 38 In the ovarian endometriomas, the levels of VEGF and cyclooxygenase 2 (COX‐2) are found to be increased and correlate with each other, implicating the role of angiogenesis in ovarian endometriosis. 39 In a systematic review and meta‐analysis on 13 published papers on animal models, anti‐VEGF/VEGF receptor therapy was found successful for treatment of endometriosis via suppression of angiogenesis. 40 Also, it has been shown that transforming growth factor β1 (TGF‐β1) was increased in the peritoneum, peritoneal fluid, ectopic endometrium, and sera of women with endometriosis in compression to the controls. 41 MMPs are among the important angiogenic factors that degrade basement membrane for facilitating the migration of endothelial cells. As mentioned above, these factors are extremely expressed in the endometriosis and the levels of their inhibitor follow a decreasing pattern. 42 As described, MMPs are involved in the pathogenesis of endometriosis secondary to the inflammation. Studies have shown impaired or increased production of MMP‐1, MMP‐2, MMP‐3, and MMP‐9 as well as tissue inhibitors of MMP‐1 (TIMP‐1) and TIMP‐2. 42
2.3.Inflammation and angiogenesis
Inflammation and angiogenesis have common pathways with each other. Inflamed tissues experience hypoxia which leads to the activation of HIF‐1α. 43 This in turn, triggers the increased expression of VEGF, VEGF receptor (VEGFR), platelet‐derived growth factor (PDGF), stromal cell‐derived factor (SDF‐1), COX‐2, and IL‐1β that are all among the angiogenic factors. 43 , 44 , 45 , 46 Interestingly, IL‐1β and COX‐2 are also among the most important players of inflammation. 43 During hypoxia, different proangiogenic factors could be upregulated via nuclear factor κB (NF‐κB) activation among which are IL‐6, TNF‐α, macrophage inflammatory protein 2 (MIP‐2), intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM). 47 Also, inflammation could end in the release of different pro‐inflammatory cytokines among which is TNF‐α, capable of inducing NF‐κB. 43 Therefore, angiogenesis and inflammation work so close with each other that inhibition of one could potentially inhibit the other. Figure 1 48 shows the role of inflammation in the pathogenesis of endometriosis and inducing angiogenesis in environment.
3.HYPOTHESIS
Since inflammation and angiogenesis are quite crucial in the pathogenesis of endometriosis, cannabidiol could be a potent candidate for treatment of this condition due to its antiangiogenic and anti‐inflammatory potential.
3.1.Cannabidiol
Cannabinoids are active compounds of plant named Cannabis sativa which has been used in medicine for long. 49 Today, these compounds are categorized into three main groups according to their origin: (I) endocannabinoids produced in body, (II) plant‐derived cannabinoids or phytocannabinoids originating from the Cannabis sativa (exocannabinoids), (III) synthetic cannabinoids synthetized in the laboratories (exocannabinoids). 30 Although different receptors have been known for cannabinoids and endocannabinoids, they exert many of their main actions through two major groups of cannabinoids receptors of cannabinoid receptor 1 (CB1) and CB2. 50 CBD is a natural non‐psychoactive cannabinoid with affinity to both CB1 and CB2 receptors. 51 In Jun 2018, CBD became the first cannabinoid which received approval of the Food and Drug Administration (FDA) of United States for two types of seizures under the brand name of Epidiolex®. 52
3.2.Cannabidiol and inflammation
As mentioned, inflammation is a crucial step in the pathogenesis of endometriosis. Data have revealed that CBD has potent anti‐inflammatory properties. Also, in a carrageenan‐induced inflammation murine model, CBD decreased COX activity as well as PGE2 and nitric oxide levels. 53 The macrophages of mouse treated with lipopolysaccharide (LPS) showed to release lower amounts of TNF‐α after treatment with CBD. 54 Moreover, similar evidence was observed in a mouse model of endotoxin‐induced uveitis which levels of TNF‐α decreased and infiltration of macrophages was inhibited. 55 Also, it has been shown that CBD could decrease the levels of IL‐1α, IL‐6, and TNF‐α in the LPS‐treated microglial cells which seems to be achieved through modulating NF‐κB. 56 In the mitogen‐activated human peripheral blood mononuclear cells (PBMC), CBD decreased IL‐1β and TNF‐α. 57 Also, in the experimental rat models for asthma, CBD has been shown to alleviate inflammation via lowering the levels of TNF‐α, IL‐4, IL‐5, IL‐6, and IL‐13. 58 , 59
3.3.Cannabidiol and angiogenesis
CBD is proven capable of decreasing endothelial cells proliferation and migration (with no toxication and apoptosis induction). These two cell processes are both crucial for angiogenesis. This effect is known to be related to the anti‐tube formation activity of CBD on endothelial cells which is very essential for angiogenesis. These results were followed by inhibition of angiogenesis in vivo in the presence of a strong angiogenic cocktail: VEGF, TNF‐α and heparin. Interestingly, CBD decreases the expression of different proangiogenic factors such as MMP‐2, MMP‐9, TIMP‐1, CXCL16, endothelin 1, IL‐8, and PDGF‐AA. 60 Also, cannabidiol hydroxyquinone (HU‐331) is able to inhibit angiogenesis in an ex vivo model of rat aortic ring (VEGF induced). Moreover, in a mouse tumor‐angiogenesis models, HU‐331 showed potential of decreasing vessels total area, density, and size. 61 Another study on human endothelial cells demonstrated that CBD decreased high glucose‐induced expression and levels of ICAM‐1 and VCAM‐1 as well as monocytes ability to adhere to the endothelial cells. Moreover, it has been stated that this cannabinoid could decrease the levels of NF‐κB. 62 As it is shown in Figure 2, both inflammation and angiogenesis are involved in the pathogenesis of endometriosis through different molecular pathways that could be inhibited by CBD.
4.CONCLUSION
So far, the exact mechanism of endometriosis is not fully understood. However, this phenomenon is known as a chronic inflammatory condition accompanied with angiogenesis. Herein, we reviewed the inflammatory aspects of this disease with an eye on angiogenesis. As we showed, the molecular pathways of angiogenesis and inflammation have a lot in common. Thus, it seems that targeting inflammation could be considered hitting two birds with one stone. Considering the potent anti‐inflammatory and antiangiogenic effects of CBD under various other conditions, authors suggest in vitro and in vivo studies on CBD and endometriosis (Figure 3).
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
Untitled section
Anvari Aliabad R, Hassanpour K, Norooznezhad AH. Cannabidiol as a Possible Treatment for Endometriosis Through Suppression of Inflammation and Angiogenesis. Immun Inflamm Dis. 2024;12:e1370. 10.1002/iid3.1370
DATA AVAILABILITY STATEMENT
All data have been used in the article.
REFERENCES
Untitled section
References
- 1. Mehedintu C, Plotogea MN, Ionescu S, Antonovici M. Endometriosis still a challenge. J Med Life. 2014;7(3):349‐357.
- 2. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261‐275.
- 3. Tanbo T, Fedorcsak P. Endometriosis‐associated infertility: aspects of pathophysiological mechanisms and treatment options. Acta Obstet Gynecol Scand. 2017;96(6):659‐667.
- 4. Liu Z. Inflammation and endometriosis. Front Biosci. 2016;21:941‐948.
- 5. Kotlyar A, Taylor HS, D'Hooghe TM. Use of immunomodulators to treat endometriosis. Best Pract Res Clin Obstet Gynaecol. 2019;60:56‐65.
- 6. Van Gorp T, Amant F, Neven P, Vergote I, Moerman P. Endometriosis and the development of malignant tumours of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol. 2004;18(2):349‐371.
- 7. Flores I, Rivera E, Ruiz LA, Santiago OI, Vernon MW, Appleyard CB. Molecular profiling of experimental endometriosis identified gene expression patterns in common with human disease. Fertil Steril. 2007;87(5):1180‐1199.
- 8. Bulun SE. Endometriosis. N Engl J Med. 2009;360(3):268‐279.
- 9. Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin‐1 in general pathology. Inflamm Regen. 2019;39:12.
- 10. Sikora J, Mielczarek‐Palacz A, Kondera‐Anasz Z. Association of the precursor of interleukin‐1β and peritoneal inflammation‐role in pathogenesis of endometriosis. J Clin Lab Anal. 2016;30(6):831‐837.
- 11. Voltolini Velho R, Halben N, Chekerov R, et al. Functional changes of immune cells: signal of immune tolerance of the ectopic lesions in endometriosis? Reprod Biomed Online. 2021;43(2):319‐328.
- 12. Anvari Aliabad R, Ghasemzadeh A, Hamdi K, Navali N, Hakimi P, Farzadi L. Investigating the efficacy of ultrasound‐guided ethanol retention technique for endometrioma sclerotherapy and its effect on pro‐inflammatory cytokine levels: a single‐arm clinical trial. Clinics. 2023;78:100224.
- 13. Peng B, Alotaibi FT, Sediqi S, Bedaiwy MA, Yong PJ. Role of interleukin‐1β in nerve growth factor expression, neurogenesis and deep dyspareunia in endometriosis. Hum Reprod. 2020;35(4):901‐912.
- 14. Bullon P, Navarro JM. Inflammasome as a key pathogenic mechanism in endometriosis. Curr Drug Targets. 2017;18(9):997‐1002.
- 15. Leavy O. Evading immunosurveillance in endometriosis. Nat Rev Immunol. 2015;15(12):729.
- 16. Tanaka T, Narazaki M, Kishimoto T. IL‐6 in inflammation, immunity, and disease. Cold Spring Harbor Perspect Biol. 2014;6(10):a016295.
- 17. Tseng JF, Ryan IP, Milam TD, et al. Interleukin‐6 secretion in vitro is up‐regulated in ectopic and eutopic endometrial stromal cells from women with endometriosis. J Clin Endocrinol Metab. 1996;81(3):1118‐1122.
- 18. Li S, Fu X, Wu T, Yang L, Hu C, Wu R. Role of Interleukin‐6 and its receptor in endometriosis. Med Sci Monit. 2017;23:3801‐3807.
- 19. Tsudo T, Harada T, Iwabe T, et al. Altered gene expression and secretion of interleukin‐6 in stromal cells derived from endometriotic tissues. Fertil Steril. 2000;73(2):205‐211.
- 20. Martínez S, Garrido N, Coperias JL, et al. Serum interleukin‐6 levels are elevated in women with minimal‐mild endometriosis. Hum Reprod. 2007;22(3):836‐842.
- 21. Idriss HT, Naismith JH. TNF? and the TNF receptor superfamily: structure‐function relationship(s). Microsc Res Tech. 2000;50(3):184‐195.
- 22. Koga K, Osuga Y, Yoshino O, et al. Elevated interleukin‐16 levels in the peritoneal fluid of women with endometriosis may be a mechanism for inflammatory reactions associated with endometriosis. Fertil Steril. 2005;83(4):878‐882.
- 23. Bersinger NA, von Roten S, Wunder DM, Raio L, Dreher E, Mueller MD. PAPP‐A and osteoprotegerin, together with interleukin‐8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. Am J Obstet Gynecol. 2006;195(1):103‐108.
- 24. Ho HN, Wu MY, Chao KH, Chen CD, Chen SU, Yang YS. Peritoneal interleukin‐10 increases with decrease in activated CD4+ T lymphocytes in women with endometriosis. Hum Reprod. 1997;12(11):2528‐2533.
- 25. Jahani M, Rezazadeh D, Mohammadi P, Abdolmaleki A, Norooznezhad A, Mansouri K. Regenerative medicine and angiogenesis; challenges and opportunities. Adv Pharm Bull. 2020;10(4):490‐501.
- 26. Mohammadi MH, Molavi B, Mohammadi S, et al. Evaluation of wound healing in diabetic foot ulcer using platelet‐rich plasma gel: a single‐arm clinical trial. Transfus Apher Sci. 2017;56(2):160‐164.
- 27. Rasouli H, Norooznezhad AH, Rashidi T, et al. Comparative in vitro/theoretical studies on the anti‐angiogenic activity of date pollen hydro‐alcoholic extract: highlighting the important roles of its hot polyphenols. Bioimpacts. 2018;8(4):281‐294.
- 28. Keshavarz M, Norooznezhad AH, Mansouri K, Mostafaie A. Cannabinoid (JWH‐133) therapy could be effective for treatment of corneal neovascularization. J Med Hypothese Ideas. 2010;4:3.
- 29. Norooznezhad F, Rodriguez‐Merchan EC, Asadi S, Norooznezhad AH. Curcumin: hopeful treatment of hemophilic arthropathy via inhibition of inflammation and angiogenesis. Expert Rev Hematol. 2020;13(1):5‐11.
- 30. Norooznezhad AH, Norooznezhad F. Cannabinoids: possible agents for treatment of psoriasis via suppression of angiogenesis and inflammation. Med Hypotheses. 2017;99:15‐18.
- 31. Symons LK, Miller JE, Kay VR, et al. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24(9):748‐762.
- 32. Kinugasa S, Shinohara K, Wakatsuki A. Increased asymmetric dimethylarginine and enhanced inflammation are associated with impaired vascular reactivity in women with endometriosis. Atherosclerosis. 2011;219(2):784‐788.
- 33. Zhu S, Wang A, Xu W, Hu L, Sun J, Wang X. The heterogeneity of fibrosis and angiogenesis in endometriosis revealed by single‐cell RNA‐sequencing. Biochim Biophys Acta Molec Basis Dis. 2023;1869(2):166602.
- 34. Bo C, Wang Y. Angiogenesis signaling in endometriosis: molecules, diagnosis and treatment (Review). Mol Med Rep. 2024;29(3):43.
- 35. Wu MH, Hsiao KY, Tsai SJ. Hypoxia: the force of endometriosis. J Obstet Gynaecol Res. 2019;45(3):532‐541.
- 36. Zhan L, Wang W, Zhang Y, Song E, Fan Y, Wei B. Hypoxia‐inducible factor‐1alpha: A promising therapeutic target in endometriosis. Biochimie. 2016;123:130‐137.
- 37. Goteri G, Lucarini G, Montik N, et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor‐1α (HIF‐1α), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Pathol. 2009;28(2):157‐163.
- 38. Goteri G, Lucarini G, Zizzi A, et al. Proangiogenetic molecules, hypoxia‐inducible factor‐1α and nitric oxide synthase isoforms in ovarian endometriotic cysts. Virchows Arch. 2010;456(6):703‐710.
- 39. Ceyhan ST, Onguru O, Baser I, Gunhan O. Expression of cyclooxygenase‐2 and vascular endothelial growth factor in ovarian endometriotic cysts and their relationship with angiogenesis. Fertil Steril. 2008;90(4):988‐993.
- 40. Liu S, Xin X, Hua T, et al. Efficacy of anti‐VEGF/VEGFR agents on animal models of endometriosis: a systematic review and Meta‐Analysis. PLoS One. 2016;11(11):e0166658.
- 41. Young VJ, Ahmad SF, Duncan WC, Horne AW. The role of TGF‐β in the pathophysiology of peritoneal endometriosis. Hum Reprod Update. 2017;23(5):548‐559.
- 42. Wu Y, Kajdacsy‐Balla A, Strawn E, et al. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology. 2006;147(1):232‐246.
- 43. Szade A, Grochot‐Przeczek A, Florczyk U, Jozkowicz A, Dulak J. Cellular and molecular mechanisms of inflammation‐induced angiogenesis. IUBMB Life. 2015;67(3):145‐159.
- 44. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF‐1 induction of SDF‐1. Nature Med. 2004;10(8):858‐864.
- 45. Zhang W, Petrovic JM, Callaghan D, et al. Evidence that hypoxia‐inducible factor‐1 (HIF‐1) mediates transcriptional activation of interleukin‐1β (IL‐1β) in astrocyte cultures. J Neuroimmunol. 2006;174(1‐2):63‐73.
- 46. Kaidi A, Qualtrough D, Williams AC, Paraskeva C. Direct transcriptional up‐regulation of cyclooxygenase‐2 by hypoxia‐inducible factor (HIF)‐1 promotes colorectal tumor cell survival and enhances HIF‐1 transcriptional activity during hypoxia. Cancer Res. 2006;66(13):6683‐6691.
- 47. Oliver KM, Taylor CT, Cummins EP. Hypoxia. Regulation of NFκB signalling during inflammation: the role of hydroxylases. Arthritis Res Ther. 2009;11(1):215.
- 48. Wei Y, Liang Y, Lin H, Dai Y, Yao S. Autonomic nervous system and inflammation interaction in endometriosis‐associated pain. J Neuroinflam. 2020;17(1):80.
- 49. Keshavarz M, Norooznezhad AH, Mansouri K, Mostafaie A. Cannabinoid (JWH‐133) therapy could be effective for treatment of corneal neovascularization. Iran J Med Hypotheses Ideas. 2010;4:3.
- 50. Norooznezhad A, Norooznezhad F, Bagheri N. Cannabinoids as treatment for hemophilic arthropathy: hypothesized molecular pathways. J Rep Pharm Sci. 2016;5(2):89‐93.
- 51. Stanley CP, Hind WH, O'Sullivan SE. Is the cardiovascular system a therapeutic target for cannabidiol? Br J Clin Pharmacol. 2013;75(2):313‐322.
- 52. Brunetti P, Lo Faro AF, Pirani F, et al. Pharmacology and legal status of cannabidiol. Ann Istit Super Sanita. 2020;56(3):285‐291.
- 53. Pellati F, Borgonetti V, Brighenti V, Biagi M, Benvenuti S, Corsi L. Cannabis sativa L. and nonpsychoactive cannabinoids: their chemistry and role against oxidative stress, inflammation, and cancer. BioMed Res Int. 2018;2018:1691428.
- 54. Ben‐Shabat S, Hanuš LO, Katzavian G, Gallily R. New cannabidiol derivatives: synthesis, binding to cannabinoid receptor, and evaluation of their antiinflammatory activity. J Med Chem. 2006;49(3):1113‐1117.
- 55. El‐Remessy AB, Tang Y, Zhu G, et al. Neuroprotective effects of cannabidiol in endotoxin‐induced uveitis: critical role of p38 MAPK activation. Mol Vision. 2008;14:2190‐2203.
- 56. Kozela E, Pietr M, Juknat A, Rimmerman N, Levy R, Vogel Z. Cannabinoids Δ9‐tetrahydrocannabinol and cannabidiol differentially inhibit the lipopolysaccharide‐activated NF‐κB and Interferon‐β/STAT proinflammatory pathways in BV‐2 microglial cells. J Biol Chem. 2010;285(3):1616‐1626.
- 57. Watzl B, Scuderi P, Watson RR. Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon‐gamma and suppress interleukin‐1 alpha in vitro. Int J Immunopharmacol. 1991;13(8):1091‐1097.
- 58. Vuolo F, Abreu SC, Michels M, et al. Cannabidiol reduces airway inflammation and fibrosis in experimental allergic asthma. Eur J Pharmacol. 2019;843:251‐259.
- 59. Vuolo F, Petronilho F, Sonai B, et al. Evaluation of serum cytokines levels and the role of cannabidiol treatment in animal model of asthma. Mediat Inflamm. 2015;2015:538670.
- 60. Solinas M, Massi P, Cantelmo A, et al. Cannabidiol inhibits angiogenesis by multiple mechanisms. Br J Pharmacol. 2012;167(6):1218‐1231.
- 61. Kogan NM, Blázquez C, Álvarez L, et al. A cannabinoid quinone inhibits angiogenesis by targeting vascular endothelial cells. Mol Pharmacol. 2006;70(1):51‐59.
- 62. Rajesh M, Mukhopadhyay P, Bátkai S, et al. Cannabidiol attenuates high glucose‐induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Heart Circul Physiol. 2007;293(1):H610‐H619.
Associated Data
Data Availability Statement
All data have been used in the article.