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Proangiogenic effect of metformin in endothelial cells is via upregulation of VEGFR1/2 and their signaling under hyperglycemia-hypoxia

Lookup NU author(s): Dr Sherin Bakhashab, Dr Fahad Ahmed, Dr Michael Glanville, Dr Jolanta Weaver



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Cardiovascular disease is the leading cause of morbidity/mortality worldwide. Metformin is the first therapy offering cardioprotection in type 2 diabetes and non-diabetic animals with unknown mechanism. We have shown that metformin improves angiogenesis via affecting expression of growth factors/angiogenic inhibitors in CD34+ cells under hyperglycemia-hypoxia. Now we studied the direct effect of physiological dose of metformin on human umbilical vein endothelial cells (HUVEC) under conditions mimicking hypoxia-hyperglycemia. HUVEC migration and apoptosis were studied after induction with euglycemia or hyperglycemia and/or CoCl2 induced hypoxia in the presence or absence of metformin. HUVEC mRNA was assayed by whole transcript microarrays. Genes were confirmed by qRT-PCR, proteins by western blot, ELISA or flow cytometry. Metformin promoted HUVEC migration and inhibited apoptosis via upregulation of vascular endothelial growth factor (VEGF) receptors (VEGFR1/R2), fatty acid binding protein 4 (FABP4), ERK/mitogen-activated protein kinase signaling, chemokine ligand 8, lymphocyte antigen 96, Rho kinase 1 (ROCK1), matrix metalloproteinase 16 (MMP16) and tissue factor inhibitor-2 under hyperglycemia-chemical hypoxia. Therefore, metformin’s dual effect in hyperglycemia-chemical hypoxia is mediated by direct effect on VEGFR1/R2 leading to activation of cell migration through MMP16 and ROCK1 upregulation, and inhibition of apoptosis by increase in phospho-ERK1/2 and FABP4, components of VEGF signaling cascades.

Publication metadata

Author(s): Bakhashab S, Ahmed F, Schulten H-J, Ahmed FW, Glanville M, Al-Qahtani MH, Weaver JU

Publication type: Article

Publication status: Published

Journal: International Journal of Molecular Sciences

Year: 2018

Volume: 19

Issue: 1

Online publication date: 19/01/2018

Acceptance date: 17/01/2018

Date deposited: 06/02/2018

ISSN (print): 1661-6596

ISSN (electronic): 1422-0067

Publisher: MDPI AG


DOI: 10.3390/ijms19010293


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