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Global Translational Medicine Resveratrol’s EC barrier protection is dependent on KLF2

states [15,16] . Therefore, the discovery of compounds that Conflict of interest
can help maintain or improve the endothelial barrier
function is of significant interest and may be helpful in the The authors have declared that no conflicts of interest exist.
treatment of diseases such as Alzheimer’s or Parkinson’s, Author contributions
where BBB impairment can contribute to worsening
neurodegenerative states. Conceptualization: Hong Shi
Formal analysis: Xianming Zhou, Lily Lin, Hong Shi
Resveratrol is a naturally occurring vasculoprotective
compound. Recently, studies have identified additional Investigation: Xianming Zhou, Hong Shi
Writing – original draft: Xianming Zhou, Lily Lin, Hong Shi
beneficial aspects and begun to outline the molecular Writing – review & editing: Lily Lin, Hong Shi
mechanisms of how resveratrol impacts endothelial
function . In the present study, we are the first to identify Ethics approval and consent to participate
[10]
KLF2 as an obligatory factor for resveratrol’s induction of
key tight junction factors and subsequent endothelial barrier All mouse studies were approved by an Institutional
protective effects. KLF2 is a highly expressed transcription Animal Care and Use Committee (IACUC) at Case Western
factor within ECs. The previous studies have demonstrated Reserve University (2011-0136) and were conducted in
that KLF2 critically regulates key aspects of vascular function accordance with the National Institutes of Health (NIH)
and disease, including vascular permeability, EC thrombotic Guide for the Care and Use of Laboratory Animals.
function, and angiogenesis. Importantly, in ECs, KLF2
has also been demonstrated to be critical for resveratrol’s Consent for publication
induction of endothelial nitric oxide synthase (eNOS) Not applicable.
and thrombomodulin (TM), both of which are known
to play critical roles in inflammation, vasoreactivity, and Availability of data
thrombosis . Taken together, these findings implicate KLF2 Data will be obtained from the corresponding author on
[12]
as a central regulator of resveratrol’s beneficial effects in ECs.
reasonable request.
In addition to promoting vascular health through EC
signaling, resveratrol’s mechanisms of action have been References
shown to involve other cell types . One limitation of our 1. Yu W, Fu YC, Wang W, 2012, Cellular and molecular effects of
[1]
studies is that they have been performed using global resveratrol in health and disease. J Cell Biochem, 113: 752–759.
KLF2-deficient mice; therefore, we cannot rule out the https://doi.org/10.1002/jcb.23431
contributing factors from non-EC sources. For that reason,
since KLF2 is also expressed in cells of the myeloid lineage, 2. Baur JA, Sinclair DA, 2006, Therapeutic potential of
future studies in mice with EC-specific KLF2 deficiency resveratrol: The in vivo evidence. Nat Rev Drug Discov,
are warranted to further pinpoint the importance of 5: 493–506.
resveratrol’s regulation of KLF2 in ECs. 3. Gresele P, Cerletti C, Guglielmini G, et al, 2011, Effects
Finally, resveratrol has been proposed to be beneficial of resveratrol and other wine polyphenols on vascular
in vascular diseases, such as atherosclerosis and ischemic function: An update. J Nutr Biochem, 22: 201–211.
stroke [1-3,5] . Similarly, we have demonstrated KLF2 to be https://doi.org/10.1016/j.jnutbio.2010.07.004
a protective factor against atherosclerosis and stroke [11,17] . 4. Schmitt CA, Heiss EH, Dirsch VM, 2010, Effect of resveratrol
Studies treating KLF2-deficient mice with resveratrol in on endothelial cell function: Molecular mechanisms.
these disease models will, further, define its mechanistic Biofactors, 36: 342–349.
pathway of action and how it, or other similar compounds, https://doi.org/10.1002/biof.109
can be used as an inexpensive and natural way to help
treat and/or alleviate symptoms associated with vascular, 5. Clark D, Tuor UI, Thompson R, et al., 2012, Protection
cerebral, or neurodegenerative disorders. against recurrent stroke with resveratrol: Endothelial
protection. PLoS One, 7: e47792.
Acknowledgments https://doi.org/10.1371/journal.pone.0047792

We thank Dr. G. Brandon Atkins for providing conditional 6. Kim YH, Kim YS, Roh GS, et al., 2012, Resveratrol blocks
KLF2-deficient mice for these studies. diabetes-induced early vascular lesions and vascular
endothelial growth factor induction in mouse retinas. Acta
Funding Ophthalmol, 90: e31–37.
None. https://doi.og/10.1111/j.1755-3768.2011.02243.x

Volume 2 Issue 1 (2023) 6 https://doi.org/10.36922/gtm.v2i1.218