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Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO
Valentina Marchetti1, Rossella Menghini, Stefano Rizza
1Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Abstract:
Dysfunction of mature endothelial cells is thought to play a major role in both micro- and macrovascular complications of diabetes. However, recent advances in biology of endothelial progenitor cells (EPCs) have highlighted their involvement in diabetes complications. To determine the effect of glucotoxicity on EPCs, human EPCs have been isolated from peripheral blood mononuclear cells of healthy donors and cultured in the presence or absence of high glucose (33 mmol/l) or high glucose plus benfotiamine to scavenge glucotoxicity. Morphological analysis revealed that high glucose significantly affected the number of endothelial cell colony forming units, uptake and binding of acLDL and Lectin-1, and the ability to differentiate into CD31- and vascular endothelial growth factor receptor 2-positive cells. Functional analysis outlined a reduced EPC involvement in de novo tube formation, when cocultured with mature endothelial cells (human umbilical vein endothelial cells) on matrigel. To explain the observed phenotypes, we have investigated the signal transduction pathways known to be involved in EPC growth and differentiation. Our results indicate that hyperglycemia impairs EPC differentiation and that the process can be restored by benfotiamine administration, via the modulation of Akt/FoxO1 activity.
Insights
High glucose impairs endothelial progenitor cells (EPCs) differentiation, crucial for blood vessel repair in diabetes. Benfotiamine treatment restored EPC function by modulating key signaling pathways.
Area of Science:
- Endothelial biology
- Diabetology
- Cellular signaling
Background:
- Endothelial cell dysfunction contributes to diabetic vascular complications.
- Endothelial progenitor cells (EPCs) play a role in vascular repair and are implicated in diabetes.
- The impact of high glucose (glucotoxicity) on EPC function requires further investigation.
Purpose of the Study:
- To investigate the effects of glucotoxicity on human endothelial progenitor cells (EPCs).
- To determine if benfotiamine can mitigate the negative effects of high glucose on EPCs.
- To explore the underlying signaling pathways affected by hyperglycemia in EPCs.
Main Methods:
- Human EPCs were isolated and cultured under high glucose conditions, with or without benfotiamine.
- Assessed EPC morphology, colony-forming capacity, acLDL/Lectin-1 uptake, and differentiation markers (CD31, VEGFR2).
- Evaluated EPC function in co-culture models of angiogenesis and analyzed Akt/FoxO1 signaling pathways.
Main Results:
- High glucose significantly reduced EPC colony formation, differentiation potential, and cell surface marker expression.
- Hyperglycemia impaired EPCs' ability to contribute to de novo tube formation in co-cultures.
- Benfotiamine treatment restored EPC differentiation and function, associated with Akt/FoxO1 pathway modulation.
Conclusions:
- Hyperglycemia adversely affects endothelial progenitor cell function and differentiation.
- Benfotiamine shows potential in ameliorating glucotoxicity-induced EPC dysfunction.
- Modulation of the Akt/FoxO1 pathway is implicated in the protective effects of benfotiamine against hyperglycemia in EPCs.
