The vasculoprotective effects of resveratrol are mediated via Kruppel-like factor 2 dependent protection of endothelial barrier function
Resveratrol is a naturally occurring polyphenolic compound that is thought to have vasculoprotective properties. Its observed effects are proposed, in part, to be mediated through the induction of endothelial Krϋppel-like factor 2 (KLF2) expression. KLF2 is a nuclear transcription factor that is highly expressed within the vascular endothelium. Studies from our laboratory and others have shown that this protein mediates vascular function through its transactivation domain, and its targeted expression promotes vascular health, notably by acting as an important positive regulator of endothelial barrier function. In this study, we demonstrate that resveratrol possesses endothelial barrier protective effects dependent on the presence of KLF2, with several key endothelial tight junction proteins expressed in a KLF2-dependent manner. Collectively, our findings identify KLF2 as essential for resveratrol-mediated endothelial barrier protection, thus further implicating KLF2 as a critical vasculoprotective factor.
Yu W, Fu YC, Wang W, 2012, Cellular and molecular effects of resveratrol in health and disease. J Cell Biochem, 113: 752–759. https://doi.org/10.1002/jcb.23431
Baur JA, Sinclair DA, 2006, Therapeutic potential of resveratrol: The in vivo evidence. Nat Rev Drug Discov, 5: 493–506.
Gresele P, Cerletti C, Guglielmini G, et al, 2011, Effects of resveratrol and other wine polyphenols on vascular function: An update. J Nutr Biochem, 22: 201–211. https://doi.org/10.1016/j.jnutbio.2010.07.004
Schmitt CA, Heiss EH, Dirsch VM, 2010, Effect of resveratrol on endothelial cell function: Molecular mechanisms. Biofactors, 36: 342–349. https://doi.org/10.1002/biof.109
Clark D, Tuor UI, Thompson R, et al., 2012, Protection against recurrent stroke with resveratrol: Endothelial protection. PLoS One, 7: e47792. https://doi.org/10.1371/journal.pone.0047792
Kim YH, Kim YS, Roh GS, et al., 2012, Resveratrol blocks diabetes-induced early vascular lesions and vascular endothelial growth factor induction in mouse retinas. Acta Ophthalmol, 90: e31–37. https://doi.og/10.1111/j.1755-3768.2011.02243.x
McConnell BB, Yang VW, 2010, Mammalian kruppel-like factors in health and diseases. Physiol Rev, 90: 1337–1381. https://doi.org/10.1152/physrev.00058.2009
Atkins GB, Jain MK, 2007, Role of kruppel-like transcription factors in endothelial biology. Circ Res, 100: 1686–1695. https://doi.org/10.1161/01.RES.0000267856.00713.0a
Sweet DR, Fan L, Hsieh PN, et al., 2018, Kruppel-like factors in vascular inflammation: Mechanistic insights and therapeutic potential. Front Cardiovasc Med, 5: 6. https://doi.org/10.3389/fcvm.2018.00006
Lin Z, Natesan V, Shi H, et al., 2010, Kruppel-like factor 2 regulates endothelial barrier function. Arterioscler Thromb Vasc Biol, 30: 1952–1959. https://doi.org/10.1161/ATVBAHA.110.211474
Shi H, Sheng B, Zhang F, et al., 2013, Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function. Am J Physiol Heart Circ Physiol, 304: H796–H805. https://doi.org/10.1152/ajpheart.00712.2012
Gracia-Sancho J, Villarreal G Jr., Zhang Y, et al., 2010, Activation of sirt1 by resveratrol induces klf2 expression conferring an endothelial vasoprotective phenotype. Cardiovasc Res, 85: 514–519. https://doi.org/10.1093/cvr/cvp337
Segarra M, Aburto MR, Acker-Palmer A, 2021, Blood-brain barrier dynamics to maintain brain homeostasis. Trends Neurosci, 44: 393–405. https://doi.org/10.1016/j.tins.2020.12.002
Monahan-Earley R, Dvorak AM, Aird WC, 2013, Evolutionary origins of the blood vascular system and endothelium. J Thromb Haemost, 11 Suppl 1: 46–66. https://doi.org/10.1111/jth.12253
Kumar P, Shen Q, Pivetti CD, et al., 2009, Molecular mechanisms of endothelial hyperpermeability: Implications in inflammation. Expert Rev Mol Med, 11: e19. https://doi.org/10.1017/S1462399409001112
Claesson-Welsh L, Dejana E, McDonald DM, 2021, Permeability of the endothelial barrier: Identifying and reconciling controversies. Trends Mol Med, 27: 314–331. https://doi.org/10.1016/j.molmed.2020.11.006
Atkins GB, Wang Y, Mahabeleshwar GH, et al., 2008, Hemizygous deficiency of kruppel-like factor 2 augments experimental atherosclerosis. Circ Res, 103: 690–693. https://doi.org/10.1161/CIRCRESAHA.108.184663