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Int. J. Mol. Sci. 2018, 19(1), 293; https://doi.org/10.3390/ijms19010293

Proangiogenic Effect of Metformin in Endothelial Cells Is via Upregulation of VEGFR1/2 and Their Signaling under Hyperglycemia-Hypoxia

1
Biochemistry Department, King Abdulaziz University, Jeddah P.O. Box 80218, Saudi Arabia
2
Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
3
Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah P.O. Box 80216, Saudi Arabia
4
Queen Elizabeth Hospital, Gateshead, Newcastle Upon Tyne NE9 6SH, UK
5
Cardiovascular Research Centre, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK
*
Author to whom correspondence should be addressed.
Received: 10 December 2017 / Revised: 12 January 2018 / Accepted: 17 January 2018 / Published: 19 January 2018
(This article belongs to the Special Issue Metformin: Mechanism and Application)
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Abstract

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. View Full-Text
Keywords: cardiovascular disease; ischemia; diabetes; VEGF signaling cardiovascular disease; ischemia; diabetes; VEGF signaling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Bakhashab, S.; Ahmed, F.; Schulten, H.-J.; Ahmed, F.W.; Glanville, M.; Al-Qahtani, M.H.; Weaver, J.U. Proangiogenic Effect of Metformin in Endothelial Cells Is via Upregulation of VEGFR1/2 and Their Signaling under Hyperglycemia-Hypoxia. Int. J. Mol. Sci. 2018, 19, 293.

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