SFEBES2009 Poster Presentations Diabetes, Metabolism and Cardiovascular (49 abstracts)
Metformin decreases angiogenesis via ERK1/2/ERK5 pathways by increasing the anti-angiogenic adipokine thrombospondin-1
Bee Tan 1 , S Prashanth Kumar 1 , Jing Chen 1 , Dennis Heutling 2 , Dan Mitchell 1 , Hendrik Lehnert 2 & Harpal Randeva 1
1University of Warwick, Coventry, UK; 2Medical Department, University of Lübeck Medical School, Lübeck, Germany.
Aims: Polycystic ovary syndrome (PCOS) is associated with insulin resistance, obesity and cardiovascular complications. Thrombospondin-1 (TSP-1) is a novel anti-angiogenic adipokine highly expressed in obese, insulin-resistant subjects. We sought to assess TSP-1 levels in adipose (AT) from PCOS women and matched controls. The effects of metformin treatment on circulating TSP-1 levels in PCOS subjects; effects of serum from normal and PCOS women on in vitro migration and angiogenesis, before and after metformin treatment; ex vivo regulation of AT TSP-1 by D-glucose were also studied.
Methods and results: Serum TSP-1 (ELISA), subcutaneous and omental AT TSP-1 mRNA (RT-PCR) and protein (western blotting) were significantly lower in PCOS women (P<0.05). Corresponding plasminogen activator inhibitor-1 (PAI-1) and PAI- activity were significantly higher (P<0.01). After 6 months of metformin treatment, there was a significant increase in serum TSP-1 (P<0.05) and a corresponding decrease in PAI-1 and PAI-1 activity (P<0.01). In vitro migration and angiogenesis were significantly increased in serum from PCOS women (P<0.01); these effects were significantly attenuated by metformin treatment (P<0.01) through the regulation of TSP-1 levels via Erk1/2 and Erk5 signaling pathways. Importantly, changes in intima media thickness were predictive of changes in serum TSP-1 (P=0.049). In AT explants, glucose significantly decreased TSP-1 protein production and secretion into conditioned media (ELISA) (P<0.05, P< 0.001).
Conclusions: TSP-1 levels are lower in PCOS women. Metformin treatment increases serum TSP-1 in these women. Our findings provide novel insights into the relationship between obesity, insulin resistance and angiogenesis.
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Endocrine Abstracts
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