Skip to main content

Advertisement

Springer Nature Link
Log in

Role of melatonin in controlling angiogenesis under physiological and pathological conditions

  • Review Paper
  • Published:
Angiogenesis Aims and scope Submit manuscript

Abstract

Angiogenesis depends on proangiogenic and anti-angiogenic molecules that regulate endothelial cell proliferation and migration. Well-regulated angiogenesis plays a pivotal role in many physiological conditions such as reproduction and embryonic development, while abnormal angiogenesis is also the basis of a variety of pathological processes including tumor metastasis and atherosclerotic plaque formation. Melatonin has a variety of biological effects, including inhibition of tumor metastasis, stabilizing atherosclerotic plaques, and the regulation of seasonal reproductive rhythms, etc. During certain pathophysiological processes, melatonin exerts different functions depending on its ability to regulate angiogenesis. This review reveals that melatonin has different effects on neovascularization under different physiological and pathological conditions. In tumors, in age-related ocular diseases, and in a hypoxic environment, melatonin inhibits neovascularization in tissues, while in gastric ulcers, skin lesions, and some physiologic processes, it promotes angiogenesis. We also speculate that melatonin may inhibit the neovascularization in atherosclerotic plaques, thus preventing the initiation and development of atherosclerosis. Most studies suggest that these effects are related to the role of melatonin in regulating of vascular endothelial growth factor and its receptors, but the specific regulatory mechanisms remain disparate, which may lead to the differential effects of melatonin on angiogenesis under different conditions. In this review, we thus summarize some seemingly contradictory mechanisms by which melatonin controls angiogenesis under different pathological and physiological conditions, and urge that the regulatory mechanisms be further studied.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chemistry 267(16):10931–10934. https://doi.org/10.1007/978-1-4613-2825-4_42

    Article  CAS  PubMed  Google Scholar 

  2. Vandekeere S, Dewerchin M, Carmeliet P (2015) Angiogenesis revisited: an overlooked role of endothelial cell metabolism in vessel sprouting. Microcirculation 22(7):509–517. https://doi.org/10.1111/micc.12229

    Article  PubMed  Google Scholar 

  3. Alvarez-Garcia V, Gonzalez A, Alonso-Gonzalez C, Martinez-Campa C, Cos S (2013) Antiangiogenic effects of melatonin in endothelial cell cultures. Microvasc Res 87:25–33. https://doi.org/10.1016/j.mvr.2013.02.008

    Article  CAS  PubMed  Google Scholar 

  4. Rizov M, Andreeva P, Dimova I (2017) Molecular regulation and role of angiogenesis in reproduction. Taiwan J Obstet Gynecol 56(2):127–132. https://doi.org/10.1016/j.tjog.2016.06.019

    Article  PubMed  Google Scholar 

  5. Gerbaud P, Murthi P, Guibourdenche J, Guimiot F, Sarazin B, Evain-Brion D, Badet J, Pidoux G (2019) Study of human T21 placenta suggests a potential role of mesenchymal spondin-2 in placental vascular development. Endocrinology 160(3):684–698. https://doi.org/10.1210/en.2018-00826

    Article  PubMed  Google Scholar 

  6. DiPietro LA (2016) Angiogenesis and wound repair: when enough is enough. J Leukoc Biol 100(5):979–984. https://doi.org/10.1189/jlb.4MR0316-102R

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ribatti D, Crivellato E (2012) "Sprouting angiogenesis", a reappraisal. Dev Biol 372(2):157–165. https://doi.org/10.1016/j.ydbio.2012.09.018

    Article  CAS  PubMed  Google Scholar 

  8. Folkman J, Cotran R (1976) Relation of vascular proliferation to tumor growth. Int Rev Exp Pathol 16:207–248

    CAS  PubMed  Google Scholar 

  9. Carmeliet P (2003) Angiogenesis in health and disease. Nat Med 9(6):653–660. https://doi.org/10.1038/nm0603-653

    Article  CAS  PubMed  Google Scholar 

  10. McCord CP, Allen FP (1917) Evidences associating pineal gland function with alterations in pigmentation. Journal of experimental zoology 23:207–224. https://doi.org/10.1002/jez.1400230108

    Article  CAS  Google Scholar 

  11. Lerner AB, Case JD, Takahashi Y, Lee TH, Mori W (1958) Isolation of melatonin the pineal gland factor that lightens melanocytes. J Am Chem Soc 80(10):2587–2587. https://doi.org/10.1021/ja01543a060

    Article  CAS  Google Scholar 

  12. Konturek SJ, Konturek PC, Brzozowska I, Pawlik M, Sliwowski Z, Czesnikiewicz-Guzik M, Kwiecien S, Brzozowski T, Bubenik GA, Pawlik WW (2007) Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). J Physiol Pharmacol 58(3):381–405

    CAS  PubMed  Google Scholar 

  13. Reiter RJ, Tan DX, Galano A (2014) Melatonin: exceeding expectations. Physiology (Bethesda) 29(5):325–333. https://doi.org/10.1152/physiol.00011.2014

    Article  CAS  Google Scholar 

  14. Claustrat B, Leston J (2015) Melatonin: physiological effects in humans. Neurochirurgie 61(2–3):77–84. https://doi.org/10.1016/j.neuchi.2015.03.002

    Article  CAS  PubMed  Google Scholar 

  15. Tan DX, Reiter RJ (2019) Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells. Melatonin Res 2(1):44–66. https://doi.org/10.32794/mr11250011

    Article  Google Scholar 

  16. Reiter RJ, Tan DX, Fuentes-Broto L (2010) Melatonin: a multitasking molecule. Prog Brain Res 181:127–151. https://doi.org/10.1016/S0079-6123(08)81008-4

    Article  CAS  PubMed  Google Scholar 

  17. Lee HY, Back K (2018) Melatonin plays a pivotal role in conferring tolerance against endoplasmic reticulum stress via mitogen-activated protein kinases and bZIP60 in Arabidopsis thaliana. Melatonin Res 1(1):94–108. https://doi.org/10.32794/mr11250006

    Article  Google Scholar 

  18. Gonzalez AG, Revilla NR, Emilio J (2019) Clinical uses of melatonin: evaluation of human trials on cancer treatment. Melatonin Res 2(2):47–69. https://doi.org/10.32794/mr11250021

    Article  Google Scholar 

  19. Pfeffer M, Korf HW, Wicht H (2018) Synchronizing effects of melatonin on diurnal and circadian rhythms. Gen Comp Endocrinol 258:215–221. https://doi.org/10.1016/j.ygcen.2017.05.013

    Article  CAS  PubMed  Google Scholar 

  20. Dominguez-Rodriguez A, Abreu-Gonzalez P, Chen Y (2019) Cardioprotection and effects of melatonin administration on cardiac ischemia reperfusion: Insight from clinical studies. Melatonin Res 2(2):100–105. https://doi.org/10.32794/mr11250024

    Article  Google Scholar 

  21. Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS, Shankar A, Ali MM, de Campos Zuccari DA (2014) Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS ONE 9(1):e85311. https://doi.org/10.1371/journal.pone.0085311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gonzalez A, Gonzalez-Gonzalez A, Alonso-Gonzalez C, Menendez-Menendez J, Martinez-Campa C, Cos S (2017) Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF. Oncol Rep 37(4):2433–2440. https://doi.org/10.3892/or.2017.5446

    Article  CAS  PubMed  Google Scholar 

  23. Ganguly K, Sharma AV, Reiter RJ, Swarnakar S (2010) Melatonin promotes angiogenesis during protection and healing of indomethacin-induced gastric ulcer: role of matrix metaloproteinase-2. J Pineal Res 49(2):130–140. https://doi.org/10.1111/j.1600-079X.2010.00776.x

    Article  CAS  PubMed  Google Scholar 

  24. Bizzarri M, Proietti S, Cucina A, Reiter RJ (2013) Molecular mechanisms of the pro-apoptotic actions of melatonin in cancer: a review. Expert Opin Ther Targets 17(12):1483–1496. https://doi.org/10.1517/14728222.2013.834890

    Article  CAS  PubMed  Google Scholar 

  25. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161(2):851–858. https://doi.org/10.1016/0006-291x(89)92678-8

    Article  CAS  PubMed  Google Scholar 

  26. Cook KM, Figg WD (2010) Angiogenesis inhibitors: current strategies and future prospects. CA Cancer J Clin 60(4):222–243. https://doi.org/10.3322/caac.20075

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shulman K, Rosen S, Tognazzi K, Manseau EJ, Brown LF (1996) Expression of vascular permeability factor (VPF/VEGF) is altered in many glomerular diseases. J Am Soc Nephrol 7(5):661–666

    CAS  PubMed  Google Scholar 

  28. Ourradi K, Blythe T, Jarrett C, Barratt SL, Welsh GI, Millar AB (2017) VEGF isoforms have differential effects on permeability of human pulmonary microvascular endothelial cells. Respir Res 18(1):116. https://doi.org/10.1186/s12931-017-0602-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shibuya M (2011) Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2(12):1097–1105. https://doi.org/10.1177/1947601911423031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ferrara N (1999) Molecular and biological properties of vascular endothelial growth factor. J Mol Med (Berl) 77(7):527–543. https://doi.org/10.1007/s001099900019

    Article  CAS  Google Scholar 

  31. Gupta K, Kshirsagar S, Li W, Gui L, Ramakrishnan S, Gupta P, Law PY, Hebbel RP (1999) VEGF prevents apoptosis of human microvascular endothelial cells via opposing effects on MAPK/ERK and SAPK/JNK signaling. Exp Cell Res 247(2):495–504. https://doi.org/10.1006/excr.1998.4359

    Article  CAS  PubMed  Google Scholar 

  32. Beazley-Long N, Hua J, Jehle T, Hulse RP, Dersch R, Lehrling C, Bevan H, Qiu Y, Lagreze WA, Wynick D, Churchill AJ, Kehoe P, Harper SJ, Bates DO, Donaldson LF (2013) VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro. Am J Pathol 183(3):918–929. https://doi.org/10.1016/j.ajpath.2013.05.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cerezo AB, Hornedo-Ortega R, Alvarez-Fernandez MA, Troncoso AM, Garcia-Parrilla MC (2017) Inhibition of VEGF-induced VEGFR-2 activation and HUVEC migration by melatonin and other bioactive indolic compounds. Nutrients 9(3):249. https://doi.org/10.3390/nu9030249

    Article  CAS  PubMed Central  Google Scholar 

  34. Ramirez-Fernandez MP, Calvo-Guirado JL, de-Val JE, Delgado-Ruiz RA, Negri B, Pardo-Zamora G, Penarrocha D, Barona C, Granero JM, Alcaraz-Banos M (2013) Melatonin promotes angiogenesis during repair of bone defects: a radiological and histomorphometric study in rabbit tibiae. Clin Oral Invest 17(1):147–158. https://doi.org/10.1007/s00784-012-0684-6

    Article  Google Scholar 

  35. Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A (2016) A review of melatonin, its receptors and drugs. Eurasian J Med 48(2):135–141. https://doi.org/10.5152/eurasianjmed.2015.0267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zonta YR, Martinez M, Camargo IC, Domeniconi RF, Lupi Junior LA, Pinheiro PF, Reiter RJ, Martinez FE, Chuffa LG (2017) Melatonin reduces angiogenesis in serous papillary ovarian carcinoma of ethanol-preferring rats. Int J Mol Sci 18(4):763

    Article  PubMed Central  Google Scholar 

  37. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186. https://doi.org/10.1056/NEJM197111182852108

    Article  CAS  PubMed  Google Scholar 

  38. Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K (2017) Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis. Int J Mol Sci 18(4):843. https://doi.org/10.3390/ijms18040843

    Article  CAS  PubMed Central  Google Scholar 

  39. Wang RX, Liu H, Xu L, Zhang H, Zhou RX (2016) Melatonin downregulates nuclear receptor RZR/RORgamma expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo. Oncol Lett 12(2):897–903. https://doi.org/10.3892/ol.2016.4729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kim KJ, Choi JS, Kang I, Kim KW, Jeong CH, Jeong JW (2013) Melatonin suppresses tumor progression by reducing angiogenesis stimulated by HIF-1 in a mouse tumor model. J Pineal Res 54(3):264–270. https://doi.org/10.1111/j.1600-079X.2012.01030.x

    Article  CAS  PubMed  Google Scholar 

  41. Carbajo-Pescador S, Ordonez R, Benet M, Jover R, Garcia-Palomo A, Mauriz JL, Gonzalez-Gallego J (2013) Inhibition of VEGF expression through blockade of Hif1alpha and STAT3 signalling mediates the anti-angiogenic effect of melatonin in HepG2 liver cancer cells. Br J Cancer 109(1):83–91. https://doi.org/10.1038/bjc.2013.285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Goradel NH, Asghari MH, Moloudizargari M, Negahdari B, Haghi-Aminjan H, Abdollahi M (2017) Melatonin as an angiogenesis inhibitor to combat cancer: mechanistic evidence. Toxicol Appl Pharmcol 335:56–63. https://doi.org/10.1016/j.taap.2017.09.022

    Article  CAS  Google Scholar 

  43. Alvarez-Garcia V, Gonzalez A, Alonso-Gonzalez C, Martinez-Campa C, Cos S (2013) Regulation of vascular endothelial growth factor by melatonin in human breast cancer cells. J Pineal Res 54(4):373–380. https://doi.org/10.1111/jpi.12007

    Article  CAS  PubMed  Google Scholar 

  44. Menendez-Menendez J, Martinez-Campa C (2018) Melatonin: an anti-tumor agent in hormone-dependent cancers. Int J Endocrinol 2018:3271948. https://doi.org/10.1155/2018/3271948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Calvo-Guirado JL, Ramirez-Fernandez MP, Gomez-Moreno G, Mate-Sanchez JE, Delgado-Ruiz R, Guardia J, Lopez-Mari L, Barone A, Ortiz-Ruiz AJ, Martinez-Gonzalez JM, Bravo LA (2010) Melatonin stimulates the growth of new bone around implants in the tibia of rabbits. J Pineal Res 49(4):356–363. https://doi.org/10.1111/j.1600-079X.2010.00801.x

    Article  CAS  PubMed  Google Scholar 

  46. Shino H, Hasuike A, Arai Y, Honda M, Isokawa K, Sato S (2016) Melatonin enhances vertical bone augmentation in rat calvaria secluded spaces. Med Oral Patol Oral Cir Bucal 21(1):e122–e126. https://doi.org/10.4317/medoral.20904

    Article  PubMed  Google Scholar 

  47. Yildirimturk S, Batu S, Alatli C, Olgac V, Firat D, Sirin Y (2016) The effects of supplemental melatonin administration on the healing of bone defects in streptozotocin-induced diabetic rats. J Appl Oral Sci 24(3):239–249. https://doi.org/10.1590/1678-775720150570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Soybir G, Topuzlu C, Odabas O, Dolay K, Bilir A, Koksoy F (2003) The effects of melatonin on angiogenesis and wound healing. Surg Today 33(12):896–901. https://doi.org/10.1007/s00595-003-2621-3

    Article  CAS  PubMed  Google Scholar 

  49. Pugazhenthi K, Kapoor M, Clarkson AN, Hall I, Appleton I (2008) Melatonin accelerates the process of wound repair in full-thickness incisional wounds. J Pineal Res 44(4):387–396. https://doi.org/10.1111/j.1600-079X.2007.00541.x

    Article  CAS  PubMed  Google Scholar 

  50. Mehraein F, Kabir K (2011) The effects of melatonin on open wounds of aged mice skin. Wounds 23(6):166–170

    PubMed  Google Scholar 

  51. Abdelraheim SR, Okasha AM, Ghany HM, Ibrahim HM (2015) Ghrelin gene expression in rats with ethanol-induced gastric ulcers: a role of melatonin. Endocr Regul 49(1):3–10

    Article  CAS  PubMed  Google Scholar 

  52. Colucci R, Fornai M, Antonioli L, Ghisu N, Tuccori M, Blandizzi C, Del Tacca M (2009) Characterization of mechanisms underlying the effects of esomeprazole on the impairment of gastric ulcer healing with addition of NSAID treatment. Dig Liver Dis 41(6):395–405. https://doi.org/10.1016/j.dld.2008.10.004

    Article  CAS  PubMed  Google Scholar 

  53. Celinski K, Konturek SJ, Konturek PC, Brzozowski T, Cichoz-Lach H, Slomka M, Malgorzata P, Bielanski W, Reiter RJ (2011) Melatonin or L-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. J Pineal Res 50(4):389–394. https://doi.org/10.1111/j.1600-079X.2011.00855.x

    Article  CAS  PubMed  Google Scholar 

  54. Konturek PC, Konturek SJ, Celinski K, Slomka M, Cichoz-Lach H, Bielanski W, Reiter RJ (2010) Role of melatonin in mucosal gastroprotection against aspirin-induced gastric lesions in humans. J Pineal Res 48(4):318–323. https://doi.org/10.1111/j.1600-079X.2010.00755.x

    Article  CAS  PubMed  Google Scholar 

  55. Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA (2007) Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol 58 Suppl 6:23–52

    CAS  PubMed  Google Scholar 

  56. Ahluwalia A, Brzozowska IM, Hoa N, Jones MK, Tarnawski AS (2018) Melatonin signaling in mitochondria extends beyond neurons and neuroprotection: Implications for angiogenesis and cardio/gastroprotection. Proc Natl Acad Sci USA 115(9):E1942-E1943. https://doi.org/10.1073/pnas.1722131115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ganguly K, Swarnakar S (2012) Chronic gastric ulceration causes matrix metalloproteinases-9 and – 3 augmentation: alleviation by melatonin. Biochimie 94(12):2687–2698. https://doi.org/10.1016/j.biochi.2012.08.004

    Article  CAS  PubMed  Google Scholar 

  58. Pradeepkumar Singh L, Vivek Sharma A, Swarnakar S (2011) Upregulation of collagenase-1 and – 3 in indomethacin-induced gastric ulcer in diabetic rats: role of melatonin. J Pineal Res 51(1):61–74. https://doi.org/10.1111/j.1600-079X.2010.00845.x

    Article  CAS  PubMed  Google Scholar 

  59. Ganguly K, Swarnakar S (2009) Induction of matrix metalloproteinase-9 and – 3 in nonsteroidal anti-inflammatory drug-induced acute gastric ulcers in mice: regulation by melatonin. J Pineal Res 47(1):43–55. https://doi.org/10.1111/j.1600-079X.2009.00687.x

    Article  CAS  PubMed  Google Scholar 

  60. Rudra DS, Pal U, Maiti NC, Reiter RJ, Swarnakar S (2013) Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 54(4):398–405. https://doi.org/10.1111/jpi.12034

    Article  CAS  PubMed  Google Scholar 

  61. Brzozowska I, Strzalka M, Drozdowicz D, Konturek SJ, Brzozowski T (2014) Mechanisms of esophageal protection, gastroprotection and ulcer healing by melatonin. implications for the therapeutic use of melatonin in gastroesophageal reflux disease (GERD) and peptic ulcer disease. Curr Pharm Des 20(30):4807–4815. https://doi.org/10.2174/1381612819666131119110258

    Article  CAS  PubMed  Google Scholar 

  62. Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294(5545):1337–1340. https://doi.org/10.1126/science.1066373

    Article  CAS  PubMed  Google Scholar 

  63. Ivan M, Haberberger T, Gervasi DC, Michelson KS, Gunzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG Jr (2002) Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc Natl Acad Sci USA 99(21):13459–13464. https://doi.org/10.1073/pnas.192342099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jardim-Perassi BV, Lourenco MR, Doho GM, Grigolo IH, Gelaleti GB, Ferreira LC, Borin TF, Moschetta MG, Pires de Campos Zuccari DA (2016) Melatonin regulates angiogenic factors under hypoxia in breast cancer cell line. Anticancer Agents Med Chem 16(3):347–358

    Article  CAS  PubMed  Google Scholar 

  65. Cheng J, Yang HL, Gu CJ, Liu YK, Shao J, Zhu R, He YY, Zhu XY, Li MQ (2019) Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1alpha/ROS/VEGF. Int J Mol Med 43(2):945–955. https://doi.org/10.3892/ijmm.2018.4021

    Article  CAS  PubMed  Google Scholar 

  66. Zhang Y, Liu Q, Wang F, Ling EA, Liu S, Wang L, Yang Y, Yao L, Chen X, Wang F, Shi W, Gao M, Hao A (2013) Melatonin antagonizes hypoxia-mediated glioblastoma cell migration and invasion via inhibition of HIF-1alpha. J Pineal Res 55(2):121–130. https://doi.org/10.1111/jpi.12052

    Article  CAS  PubMed  Google Scholar 

  67. Sohn EJ, Won G, Lee J, Lee S, Kim SH (2015) Upregulation of miRNA3195 and miRNA374b mediates the anti-angiogenic properties of melatonin in hypoxic PC-3 prostate cancer cells. J Cancer 6(1):19–28. https://doi.org/10.7150/jca.9591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Goncalves Ndo N, Rodrigues RV, Jardim-Perassi BV, Moschetta MG, Lopes JR, Colombo J, Zuccari DA (2014) Molecular markers of angiogenesis and metastasis in lines of oral carcinoma after treatment with melatonin. Anticancer Agents Med Chem 14(9):1302–1311

    Article  PubMed  Google Scholar 

  69. Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005) Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1(6):401–408. https://doi.org/10.1016/j.cmet.2005.05.001

    Article  CAS  PubMed  Google Scholar 

  70. Guzy RD, Schumacker PT (2006) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91(5):807–819. https://doi.org/10.1113/expphysiol.2006.033506

    Article  CAS  PubMed  Google Scholar 

  71. Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW, Kim YJ (2010) Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res 48(2):178–184. https://doi.org/10.1111/j.1600-079X.2009.00742.x

    Article  CAS  PubMed  Google Scholar 

  72. Cho SY, Lee HJ, Jeong SJ, Lee HJ, Kim HS, Chen CY, Lee EO, Kim SH (2011) Sphingosine kinase 1 pathway is involved in melatonin-induced HIF-1alpha inactivation in hypoxic PC-3 prostate cancer cells. J Pineal Res 51(1):87–93. https://doi.org/10.1111/j.1600-079X.2011.00865.x

    Article  CAS  PubMed  Google Scholar 

  73. Vriend J, Reiter RJ (2016) Melatonin and the von Hippel-Lindau/HIF-1 oxygen sensing mechanism: a review. Biochim Biophys Acta 1865(2):176–183. https://doi.org/10.1016/j.bbcan.2016.02.004

    Article  CAS  PubMed  Google Scholar 

  74. Dorrell M, Uusitalo-Jarvinen H, Aguilar E, Friedlander M (2007) Ocular neovascularization: basic mechanisms and therapeutic advances. Surv Ophthalmol 52 Suppl 1:S3–S19. https://doi.org/10.1016/j.survophthal.2006.10.017

    Article  PubMed  Google Scholar 

  75. Amaral J, Becerra SP (2010) Effects of human recombinant PEDF protein and PEDF-derived peptide 34-mer on choroidal neovascularization. Invest Ophthalmol Vis Sci 51(3):1318–1326. https://doi.org/10.1167/iovs.09-4455

    Article  PubMed  PubMed Central  Google Scholar 

  76. Du H, Sun X, Guma M, Luo J, Ouyang H, Zhang X, Zeng J, Quach J, Nguyen DH, Shaw PX, Karin M, Zhang K (2013) JNK inhibition reduces apoptosis and neovascularization in a murine model of age-related macular degeneration. Proc Natl Acad Sci USA 110(6):2377–2382. https://doi.org/10.1073/pnas.1221729110

    Article  PubMed  PubMed Central  Google Scholar 

  77. Sakamoto K, Liu C, Tosini G (2004) Circadian rhythms in the retina of rats with photoreceptor degeneration. J Neurochem 90(4):1019–1024. https://doi.org/10.1111/j.1471-4159.2004.02571.x

    Article  CAS  PubMed  Google Scholar 

  78. Crooke A, Huete-Toral F, Colligris B, Pintor J (2017) The role and therapeutic potential of melatonin in age-related ocular diseases. J Pineal Res 63(2):e12430. https://doi.org/10.1111/jpi.12430

  79. Kaur C, Sivakumar V, Yong Z, Lu J, Foulds WS, Ling EA (2007) Blood-retinal barrier disruption and ultrastructural changes in the hypoxic retina in adult rats: the beneficial effect of melatonin administration. J Pathol 212(4):429–439. https://doi.org/10.1002/path.2195

    Article  CAS  PubMed  Google Scholar 

  80. Lv XD, Liu S, Cao Z, Gong LL, Feng XP, Gao QF, Wang J, Hu L, Cheng XC, Yu CH, Xing YQ (2016) Correlation between serum melatonin and aMT6S level for age-related macular degeneration patients. Eur Rev Med Pharmacol Sci 20(20):4196–4201

    PubMed  Google Scholar 

  81. Blasiak J, Reiter RJ, Kaarniranta K (2016) Melatonin in retinal physiology and pathology: the case of age-related macular degeneration. Oxidative Med Cell Long. https://doi.org/10.1155/2016/6819736

    Article  Google Scholar 

  82. Dehdashtian E, Mehrzadi S, Yousefi B, Hosseinzadeh A, Reiter RJ, Safa M, Ghaznavi H, Naseripour M (2018) Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sci 193:20–33. https://doi.org/10.1016/j.lfs.2017.12.001

    Article  CAS  PubMed  Google Scholar 

  83. Arranz-Romera A, Davis BM, Bravo-Osuna I, Esteban-Perez S, Molina-Martinez IT, Shamsher E, Ravindran N, Guo L, Cordeiro MF, Herrero-Vanrell R (2019) Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma. J Control Release 297:26–38. https://doi.org/10.1016/j.jconrel.2019.01.012

    Article  CAS  PubMed  Google Scholar 

  84. Calderon GD, Juarez OH, Hernandez GE, Punzo SM, De la Cruz ZD (2017) Oxidative stress and diabetic retinopathy: development and treatment. Eye 31(8):1122–1130. https://doi.org/10.1038/eye.2017.64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang J, Xu X, Elliott MH, Zhu M, Le YZ (2010) Muller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes 59(9):2297–2305. https://doi.org/10.2337/db09-1420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wang JJ, Zhu M, Le YZ (2015) Functions of Muller cell-derived vascular endothelial growth factor in diabetic retinopathy. World J Diabetes 6(5):726–733. https://doi.org/10.4239/wjd.v6.i5.726

    Article  PubMed  PubMed Central  Google Scholar 

  87. Bai Y, Ma JX, Guo J, Wang J, Zhu M, Chen Y, Le YZ (2009) Muller cell-derived VEGF is a significant contributor to retinal neovascularization. J Pathol 219(4):446–454. https://doi.org/10.1002/path.2611

    Article  CAS  PubMed  Google Scholar 

  88. Kaur C, Sivakumar V, Foulds WS, Luu CD, Ling EA (2009) Cellular and vascular changes in the retina of neonatal rats after an acute exposure to hypoxia. Invest Ophthalmol Vis Sci 50(11):5364–5374. https://doi.org/10.1167/iovs.09-3552

    Article  PubMed  Google Scholar 

  89. Jiang T, Chang Q, Zhao Z, Yan S, Wang L, Cai J, Xu G (2012) Melatonin-mediated cytoprotection against hyperglycemic injury in Muller cells. PLoS ONE 7(12):e50661. https://doi.org/10.1371/journal.pone.0050661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hellings WE, Peeters W, Moll FL, Piers SR, van Setten J, Van der Spek PJ, de Vries JP, Seldenrijk KA, De Bruin PC, Vink A, Velema E, de Kleijn DP, Pasterkamp G (2010) Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation 121(17):1941–1950. https://doi.org/10.1161/CIRCULATIONAHA.109.887497

    Article  PubMed  Google Scholar 

  91. Crea F, Libby P (2017) Acute coronary syndromes: the way forward from mechanisms to precision treatment. Circulation 136(12):1155–1166. https://doi.org/10.1161/CIRCULATIONAHA.117.029870

    Article  PubMed  PubMed Central  Google Scholar 

  92. Chistiakov DA, Orekhov AN, Bobryshev YV (2015) Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability. Acta Physiol (Oxf) 213(3):539–553. https://doi.org/10.1111/apha.12438

    Article  CAS  Google Scholar 

  93. Sedding DG, Boyle EC, Demandt JAF, Sluimer JC, Dutzmann J, Haverich A, Bauersachs J (2018) Vasa vasorum angiogenesis: key player in the initiation and progression of atherosclerosis and potential target for the treatment of cardiovascular disease. Front Immunol 9:706. https://doi.org/10.3389/fimmu.2018.00706

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Jaipersad AS, Lip GY, Silverman S, Shantsila E (2014) The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 63(1):1–11. https://doi.org/10.1016/j.jacc.2013.09.019

    Article  CAS  PubMed  Google Scholar 

  95. Favero G, Rodella LF, Reiter RJ, Rezzani R (2014) Melatonin and its atheroprotective effects: a review. Molecular cellular endocrinology 382(2):926–937. https://doi.org/10.1016/j.mce.2013.11.016

    Article  CAS  PubMed  Google Scholar 

  96. Zhang Y, Koradia A, Kamato D, Popat A, Little PJ, Ta HT (2019) Treatment of atherosclerotic plaque: perspectives on theranostics. J Pharm Pharmacol 71(7):1029–1043. https://doi.org/10.1111/jphp.13092

    Article  CAS  PubMed  Google Scholar 

  97. Ding S, Lin N, Sheng X, Zhao Y, Su Y, Xu L, Tong R, Yan Y, Fu Y, He J, Gao Y, Yuan A, Ye L, Reiter RJ, Pu J (2019) Melatonin stabilizes rupture-prone vulnerable plaques via regulating macrophage polarization in a nuclear circadian receptor RORalpha-dependent manner. Journal of pineal research:e12581. https://doi.org/10.1111/jpi.12581

    Article  Google Scholar 

  98. Li H, Li J, Jiang X, Liu S, Liu Y, Chen W, Yang J, Zhang C, Zhang W (2019) Melatonin enhances atherosclerotic plaque stability by inducing prolyl-4-hydroxylase alpha1 expression. J Hypertens 37(5):964–971. https://doi.org/10.1097/HJH.0000000000001979

    Article  CAS  PubMed  Google Scholar 

  99. Ma S, Chen J, Feng J, Zhang R, Fan M, Han D, Li X, Li C, Ren J, Wang Y, Cao F (2018) Melatonin ameliorates the progression of atherosclerosis via mitophagy activation and NLRP3 inflammasome inhibition. Oxidative Med Cell Long 2018:9286458. https://doi.org/10.1155/2018/9286458

  100. Hussein MR, Ahmed OG, Hassan AF, Ahmed MA (2007) Intake of melatonin is associated with amelioration of physiological changes, both metabolic and morphological pathologies associated with obesity: an animal model. Int J Exp Pathol 88(1):19–29. https://doi.org/10.1111/j.1365-2613.2006.00512.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Pita ML, Hoyos M, Martin-Lacave I, Osuna C, Fernandez-Santos JM, Guerrero JM (2002) Long-term melatonin administration increases polyunsaturated fatty acid percentage in plasma lipids of hypercholesterolemic rats. J Pineal Res 32(3):179–186. https://doi.org/10.1034/j.1600-079x.2002.1o851.x

    Article  CAS  PubMed  Google Scholar 

  102. Sartori C, Dessen P, Mathieu C, Monney A, Bloch J, Nicod P, Scherrer U, Duplain H (2009) Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice. Endocrinology 150(12):5311–5317. https://doi.org/10.1210/en.2009-0425

    Article  CAS  PubMed  Google Scholar 

  103. Cardinali DP, Cano P, Jimenez-Ortega V, Esquifino AI (2011) Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology 93(3):133–142. https://doi.org/10.1159/000324699

    Article  CAS  PubMed  Google Scholar 

  104. Kwon TG, Lerman LO, Lerman A (2015) The vasa vasorum in atherosclerosis: the vessel within the vascular wall. J Am Coll Cardiol 65(23):2478–2480. https://doi.org/10.1016/j.jacc.2015.04.032

    Article  PubMed  Google Scholar 

  105. Castle-Miller J, Bates DO, Tortonese DJ (2017) Mechanisms regulating angiogenesis underlie seasonal control of pituitary function. Proc Natl Acad Sci U S A 114(12):E2514–E2523. https://doi.org/10.1073/pnas.1618917114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Korf HW (2018) Signaling pathways to and from the hypophysial pars tuberalis, an important center for the control of seasonal rhythms. Gen Comp Endocrinol 258:236–243. https://doi.org/10.1016/j.ygcen.2017.05.011

    Article  CAS  PubMed  Google Scholar 

  107. Reiter RJ (1980) The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1(2):109–131. https://doi.org/10.1210/edrv-1-2-109

    Article  CAS  PubMed  Google Scholar 

  108. Reiter RJ, Tan DX, Kim SJ, Cruz MH (2014) Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow-Robin perivascular spaces. Brain Struct Funct 219(6):1873–1887. https://doi.org/10.1007/s00429-014-0719-7

    Article  CAS  PubMed  Google Scholar 

  109. Reiter RJ (1993) The melatonin rhythm: both a clock and a calendar. Experientia 49(8):654–664. https://doi.org/10.1007/BF01923947

    Article  CAS  PubMed  Google Scholar 

  110. Basini G, Bussolati S, Ciccimarra R, Grasselli F (2017) Melatonin potentially acts directly on swine ovary by modulating granulosa cell function and angiogenesis. Reprod Fertil Dev 29(12):2305–2312. https://doi.org/10.1071/RD16513

    Article  CAS  PubMed  Google Scholar 

  111. Kandemir YB, Konuk E, Katirci E, Xxx F, Behram M (2019) Is the effect of melatonin on vascular endothelial growth factor receptor-2 associated with angiogenesis in the rat ovary? Clinics 74:e658. https://doi.org/10.6061/clinics/2019/e658

    Article  PubMed  PubMed Central  Google Scholar 

  112. Li Y, Fang L, Yu Y, Shi H, Wang S, Guo Y, Sun Y (2019) Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence. Reprod Biol Endocrinol 17(1):37. https://doi.org/10.1186/s12958-019-0479-6

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81827808 and 81870178)

Author information

Authors and Affiliations

  1. Department of Cardiology, Chinese PLA General Hospital, Beijing, 100853, China

    Qiang Ma & Yundai Chen

  2. Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, Texas, 78229, USA

    Qiang Ma & Russel J. Reiter

Authors
  1. Qiang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Russel J. Reiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yundai Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Russel J. Reiter or Yundai Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, Q., Reiter, R.J. & Chen, Y. Role of melatonin in controlling angiogenesis under physiological and pathological conditions. Angiogenesis 23, 91–104 (2020). https://doi.org/10.1007/s10456-019-09689-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10456-019-09689-7

Keywords

Search

Navigation