Evidence of endothelial dysfunction in a rat model of PCOS: increased constrictor prostaglandin activity, reversible through cox inhibition

Abstract

To characterize endothelial function in resistance arteries in a novel model of PCOS. Animal model, in vitro studies Female rats were randomized at 3-4 weeks to implantation of a 7.5 mg, 90-day dihydrotestosterone (DHT) pellet (n = 24) or a matched placebo (n = 24) as previously described by Manneras et al, 2007 (a rat model exhibiting both metabolic and ovarian aspects of PCOS). At 15-16 weeks, experiments were performed on isolated mesenteric arteries using a pressurized arteriograph. Endothelial function was assessed by the response (efficacy) of pre-constricted arteries to acetylcholine (ACh) in the absence and presence of inhibitors for COX (indomethacin) and the thromboxane prostanoid receptor antagonist(SQ29,548). Distensibility was assessed by measuring vessel diameter from 3-100mmHg. Serum steroid levels were analyzed by sensitive RIA. Differences between groups were determined by ANOVA. DHT rats cycled irregularly and had significantly reduced efficacy to ACh and reduced distensibility compared to controls. Within DHT animals, maximal dilation correlated negatively to DHT levels (r2 = 0.58), but not to weight. Pre-incubation with either indomethacin or SC29,548 abrogated the dysfunction and restored full efficacy to ACh(p<0.05).Tabled 1ControlPCOSP valueWeight (g)232 ± 6299 ± 7<0.001Blood pressure (mmHg)122/85137/98<0.001Estradiol (pg/ml)4.6 ± 0.53.6 ± 0.60.218DHT (pg/ml)31 ± 3253 ± 17<0.001Mesenteric artery diameter at 50mmHg (μm)227 ± 8212 ± 40.07Efficacy (%maximal dilation)100 ± 0.178 ± 6.0<0.05Distensibility (%)235 ± 33137 ± 10<0.05Values expressed as mean ± SE. Open table in a new tab Values expressed as mean ± SE. Clinically, PCOS is associated with endothelial dysfunction, a pathologic state widely believed to be a hallmark of vascular disease. This is the first report to demonstrate endothelial dysfunction in a hyperandrogenic rat model of PCOS, and to identify the role of vasoconstrictor prostanoids, allowing for more targeted research regarding the development of disease and potential therapeutic interventions.