Metformin is the first-line drug in the treatment of type 2 diabetes worldwide based on its effectiveness and cardiovascular safety. Currently metformin is increasingly used during pregnancy in women with gestational diabetes mellitus, even if the long-term effects of metformin on offspring are not exactly known. We have previously shown that high glucose concentration increases hyaluronan (HA) production of cultured human vascular smooth muscle cells (VSMC) via stimulating the expression of hyaluronan synthase 2 (HAS2). This offers a potential mechanism whereby hyperglycemia leads to vascular macroangiopathy. In this study, we examined whether gestational metformin use affects HA content in the aortic wall of mouse offspring in vivo. We also examined the effect of metformin on HA synthesis by cultured human VSMCs in vitro. We found that gestational metformin use significantly decreased HA content in the intima-media of mouse offspring aortas. In accordance with this, the synthesis of HA by VSMCs was also significantly decreased in response to treatment with metformin. This decrease in HA synthesis was shown to be due to the reduction of both the expression of HAS2 and the amount of HAS substrates, particularly UDP-N-acetylglucosamine. As shown here, gestational metformin use is capable to program reduced HA content in the vascular wall of the offspring strongly supporting the idea, that metformin possesses long-term vasculoprotective effects.
- diabetes mellitus
- vascular remodeling
- medical research
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Contributors AS and HJ contributed to the study design, manuscript preparation and drafting the manuscript. AS, PT, SO, and SPS contributed to the data collection, analysis and revising the manuscript for important content. HSM, MK, and MS contributed to the study design and data collection. All authors read and approved the final manuscript.
Funding The work was supported by the Research Funds of Turku University and University Hospital, Satakunta Central Hospital, and Aarne Koskelo Foundation.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The study scheme was approved by the Finnish Animal Experiment Board.
Provenance and peer review Not commissioned; internally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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