OBESITY DIMINISHES THE ANTI-CONTRACTILE EFFECT OF PERIVASCULAR ADIPOSE TISSUE FUNCTION IN POST-PARTUM RATS

Objective: Obesity has detrimental effects on health and can lead to increased blood pressure, a major risk factor for cardiovascular disease. Perivascular adipose tissue (PVAT) has an anti-contractile effect which is lost in obesity. The aim of this study was to determine the effect of obesity on PVAT function in pregnancy which has not been studied previously.

Design and method: 8-week old female Sprague Dawley rats were fed a 10% fat diet (controls) or an obesogenic, high fat diet (HFD; 45% fat)for 12 weeks before mating and during pregnancy and lactation; they were killed three weeks post-partum. PVAT-intact or -denuded mesenteric arteries were mounted on a wire myograph. Cumulative concentration-response curves were constructed to the thromboxane A2 receptor agonist U46619 in the absence or presence of A769662, an activator of AMP-activated kinase (AMPK), and/or L-NMMA, a nitric oxide synthase (NOS) inhibitor.

Results: Body weight (BW), systolic and diastolic blood pressure were all significantly increased in HFD dams (BW: 391 ±11g, n=6) compared to controls (BW: 348 ±13g, n=6, p<0.05). In the absence of PVAT, contractions to U46619 were significantly smaller in artery segments from obese than in those from control dams, although the difference was eliminated after NOS inhibition. PVAT only exerted an anti-contractile effect in vessels from control dams and this effect was abolished by L-NMMA. In both the presence and absence of PVAT, 10 µM A769662 almosteliminated contractions to U46619 in vessels from obese dams (each p<0.001, n=6) and this anti-contractile effect was not modified by the NOS inhibitor. In contrast, the smaller anticontractile effect of the AMPK activator in vessels from control dams was totally abolished by 100µM L-NMMA (each p<0.0001, n=6).

Conclusions: Enhanced release of NO from the endothelium appears to be responsible for the reduced contractility of obese dam vessels relative to controls. PVAT has an anticontractile effect in control vessels which is due to NO. The loss of the PVAT effect and the NO component of the AMPK response in vessels from obese dams may relate to the highbackground, endothelial-derived NO. Nevertheless, there appears to be up-regulation or development of an additional mechanism by which AMPKhas a powerful anti-contractile effect in the mesenteric artery from obese dams.The nature of the additional mechanism is currently under investigation.

Acknowledgements: This study was funded by the British Heart Foundation (FS/12/68/30006).