Protective effects of luteolin on the venous endothelium


Luteolin is a flavonoid with antioxidant properties already demonstrated in studies related to inflammation, tumor, and cardiovascular processes; however, there are no available information regarding its antioxidant effects at the venous endothelial site. We investigated the effects of luteolin (10, 20, and 50 μmol/L) in cultures of rat venous endothelial cells. Nitric oxide (NO) and reactive oxygen species (ROS) were analyzed by fluorimetry; 3-nitrotyrosine (3-NT) residues were evaluated by immunofluorescence, and prostacyclin (PGI2) release was investigated by colorimetry. Intracellular NO levels were significantly enhanced after 10 min of luteolin incubation, with a parallel decrease in ROS generation. These results were accompanied by a significant reduction in the expression of 3-NT residues and enhanced PGI2 rates. Therefore, luteolin is effective in reducing ROS thereby improving NO availability in venous endothelial cells. Besides, luteolin-induced decrease in 3-NT residues may correlate with the enhancement in endothelial PGI2 bioavailability. These findings suggest the future application of this flavonoid as a protective agent by improving endothelial function in several circulatory disorders related to venous insufficiency.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8


  1. 1.

    Nabavi SF, Braidy N, Gortzi O et al (2015) Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull 119:1–11.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Luo Y, Shang P, Li D (2017) Luteolin: a flavonoid that has multiple cardio-protective effects and its molecular mechanisms. Front Pharmacol 8:1–10.

    CAS  Article  Google Scholar 

  3. 3.

    Cordaro M, Cuzzocrea S, Crupi R (2020) An update of palmitoylethanolamide and luteolin effects in preclinical and clinical studies of neuroinflammatory events. Antioxidants 9:216.

    CAS  Article  PubMed Central  Google Scholar 

  4. 4.

    Yi L, Chen CY, Jin X et al (2012) Differential suppression of intracellular reactive oxygen species-mediated signaling pathway in vascular endothelial cells by several subclasses of flavonoids. Biochimie 94:2035–2044.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Duarte J, Francisco V, Perez-Vizcaino F (2014) Modulation of nitric oxide by flavonoids. Food Funct 5:1653–1668.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    López-López G, Moreno L, Cogolludo A et al (2004) Nitric oxide (NO) scavenging and NO protecting effects of quercetin and their biological significance in vascular smooth muscle. Mol Pharmacol 65:851–859.

    Article  PubMed  Google Scholar 

  7. 7.

    Versari D, Daghini E, Virdis A et al (2009) Endothelium-dependent contractions and endothelial dysfunction in human hypertension. Br J Pharmacol 157:527–536.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Félétou M, Huang Y, Vanhoutte PM (2011) Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol 164:894–912.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Vanhoutte PM, Zhao Y, Xu A, Leung SWS (2016) Thirty years of saying NO. Circ Res 119:375–396.

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Tang EHC, Vanhoutte PM (2008) Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension. Physiol Genomics 32:409–418.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Feletou M, Tang EHC, Vanhoutte PM (2008) Nitric oxide the gatekeeper of endothelial vasomotor control. Front Biosci 13:4198–4217.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ischiropoulos H (2009) Protein tyrosine nitration—an update. Arch Biochem Biophys 484:117–121.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Forman HJ, Ursini F, Maiorino M (2014) An overview of mechanisms of redox signaling. J Mol Cell Cardiol 73:2–9.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Rothe CF (1993) Mean circulatory filling pressure: its meaning and measurement. J Appl Physiol 74:499–509.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Ward AO, Caputo M, Angelini GD et al (2017) Activation and inflammation of the venous endothelium in vein graft disease. Atherosclerosis 265:266–274.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Trindade MR, Assunção HCR, Torres TC et al (2018) Venous endothelium reactivity to angiotensin II: a study in primary endothelial cultures of rat vena cava and portal vein. Exp Cell Res 362:188–194.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Nakatsubo N, Kojima H, Kikuchi K et al (1998) Direct evidence of nitric oxide production from bovine aortic endothelial cells using new fluorescence indicators: diaminofluoresceins. FEBS Lett 427:263–266.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Bindokas VP, Jordán J, Lee CC, Miller RJ (1996) Superoxide production in rat hippocampal neurons: selective imaging with hydroethidine. J Neurosci 16:1324–1336.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Pueyo ME, Gonzalez W, Nicoletti A et al (2000) Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-κB activation induced by intracellular oxidative stress. Arterioscler Thromb Vasc Biol 20:645–651.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Seelinger G, Merfort I, Schempp CM (2008) Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 74:1667–1677.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Nakayama A, Morita H, Nakao T et al (2015) A food-derived flavonoid luteolin protects against angiotensin II-induced cardiac remodeling. PLoS One 10:1–15.

    CAS  Article  Google Scholar 

  22. 22.

    Su J, Xu HT, Yu JJ et al (2015) Luteolin ameliorates hypertensive vascular remodeling through inhibiting the proliferation and migration of vascular smooth muscle cells. Evidence-Based Complementary Altern Med 2015:364876.

    Article  Google Scholar 

  23. 23.

    Kamkaew N, Paracha TU, Ingkaninan K et al (2019) Vasodilatory effects and mechanisms of action of bacopa monnieri active compounds on rat mesenteric arteries. Molecules 24:1–11.

    CAS  Article  Google Scholar 

  24. 24.

    Jiang H, Xia Q, Wang X et al (2005) Luteolin induces vasorelaxion in rat thoracic aorta via calcium and potassium channels. Pharmazie 60:444–447

    CAS  PubMed  Google Scholar 

  25. 25.

    Si H, Wyeth RP, Liu D (2014) The flavonoid luteolin induces nitric oxide production and arterial relaxation. Eur J Nutr 53:269–275.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Wu J, Xu X, Li Y et al (2014) Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells. Eur J Pharmacol 745:59–68.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Ou HC, Pandey S, Hung MY et al (2019) Luteolin: a natural flavonoid enhances the survival of HUVECs against oxidative stress by modulating AMPK/PKC pathway. Am J Chin Med 47:541–557.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Abbasi N, Akhavan MM, Rahbar-Roshandel N, Shafiei M (2014) The effects of low and high concentrations of luteolin on cultured human endothelial cells under normal and glucotoxic conditions: involvement of integrin-linked kinase and cyclooxygenase-2. Phytother Res 28:1301–1307.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    El-Bassossy HM, Abo-Warda SM, Fahmy A (2013) Chrysin and luteolin attenuate diabetes-induced impairment in endothelial-dependent relaxation: effect on lipid profile, AGEs and NO generation. Phyther Res 27:1678–1684.

    CAS  Article  Google Scholar 

  30. 30.

    Gentile D, Fornai M, Pellegrini C et al (2018) Luteolin prevents cardiometabolic alterations and vascular dysfunction in mice with HFD-induced obesity. Front Pharmacol 9:1–13.

    CAS  Article  Google Scholar 

  31. 31.

    Zhu M, Chen D, Li D et al (2013) Luteolin inhibits angiotensin II-induced human umbilical vein endothelial cell proliferation and migration through downregulation of src and Akt phosphorylation. Circ J 77:772–779.

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Matsuo M, Sasaki N, Saga K, Kaneko T (2005) Cytotoxicity of flavonoids toward cultured normal human cells. Biol Pharm Bull 28:253–259.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Yi L, Jin X, Chen CY et al (2011) Chemical structures of 4-oxo-flavonoids in relation to inhibition of oxidized low-density lipoprotein (LDL)-induced vascular endothelial dysfunction. Int J Mol Sci 12:5471–5489.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Fernandes DC, Wosniak J, Pescatore LA et al (2006) Analysis of DHE-derived oxidation products by HPLC in the assessment of superoxide production and NADPH oxidase activity in vascular systems. AJP Cell Physiol 292:C413–C422.

    CAS  Article  Google Scholar 

  35. 35.

    Nazarewicz RR, Bikineyeva A, Dikalov SI (2013) Rapid and specific measurements of superoxide using fluorescence spectroscopy. J Biomol Screen 18:498–503.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Tarpey MM, Beckman JS, Ischiropoulos H et al (1995) Peroxynitrite stimulates vascular smooth muscle cell cyclic GMP synthesis. FEBS Lett 364:314–318.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Zou MH, Ullrich V (1996) Peroxynitrite formed by simultaneous generation of nitric oxide and superoxide selectively inhibits bovine aortic prostacyclin synthase. FEBS Lett 382:101–104.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Zou M, Martin C, Ullrich V (1997) Tyrosine nitration as a mechanism of selective inactivation of prostacyclin synthase by peroxynitrite. Biol Chem 378:707–713.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Zou MH (2007) Peroxynitrite and protein tyrosine nitration of prostacyclin synthase. Prostaglandins Other Lipid Mediators 82:119–127.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Polagruto JA, Schramm DD, Wang-Polagruto JF et al (2003) Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function. J Med Food 6:301–308.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Rubira MC, Consolim-Colombo FM, Rabelo ER et al (2007) Venous or arterial endothelium evaluation for early cardiovascular dysfunction in hypertensive patients? J Clin Hypertens (Greenwich) 9:859–865.

    Article  Google Scholar 

  43. 43.

    Gresele P, Momi S, Migliacci R (2010) Endothelium, venous thromboembolism and ischaemic cardiovascular events. Thromb Haemost 103:56–61.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Newby AC, Zaltsman AB (2000) Molecular mechanisms in intimal hyperplasia. J Pathol 190:300–309.<300::AID-PATH596>3.0.CO;2-I

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Sabik JF (2011) Understanding saphenous vein graft patency. Circulation 124:273–275.

    Article  PubMed  Google Scholar 

  46. 46.

    Pocock ES, Alsaigh T, Mazor R, Schmid-Schönbein GW (2014) Cellular and molecular basis of venous insufficiency. Vasc Cell 6:1–8.

    CAS  Article  Google Scholar 

  47. 47.

    Horecka A, Biernacka J, Hordyjewska A et al (2018) Antioxidative mechanism in the course of varicose veins. Phlebology 33:464–469.

    Article  PubMed  Google Scholar 

  48. 48.

    Szasz T, Thakali K, Fink GD, Watts SW (2007) A comparison of arteries and veins in oxidative stress: producers, destroyers, function, and disease. Exp Biol Med 232:27–37.

    CAS  Article  Google Scholar 

Download references


The authors are grateful to Wilson Dias Segura for technical assistance. This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2017/22028-5; 2017/21834-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).


This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (2017/22028-5; 2017/21834-8), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Author information




H.C.R.A.: Conceptualization; Methodology; Investigation. Y.M.C.C.: Conceptualization; Methodology; Investigation. J.S.B.: Conceptualization; Methodology; Investigation. R.C.T.G.: Conceptualization; Visualization; Funding acquisition. L.F.: Writing—Review & Editing; Supervision; Project administration; Funding acquisition.

Corresponding author

Correspondence to Liliam Fernandes.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures were approved and performed in accordance with the guidelines of the Ethics Committee of UNIFESP (Protocol No. 2689270319).

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

Verify currency and authenticity via CrossMark

Cite this article

Assunção, H.C.R., Cruz, Y.M.C., Bertolino, J.S. et al. Protective effects of luteolin on the venous endothelium. Mol Cell Biochem (2021).

Download citation


  • Luteolin
  • Venous endothelium
  • Nitric oxide
  • Superoxide
  • 3-NT
  • Prostacyclin