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.