Next Article in Journal
Seed Endophyte Microbiome of Crotalaria pumila Unpeeled: Identification of Plant-Beneficial Methylobacteria
Previous Article in Journal
Growth Hormone (GH) and Cardiovascular System
Article Menu
Issue 1 (January) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2018, 19(1), 293; doi: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)
View Full-Text   |   Download PDF [2577 KB, uploaded 19 January 2018]   |  

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
Figures

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).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

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.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top