Endothelial dysfunction in a rat model of PCOS: evidence of increased vasoconstrictor prostanoid activity.
Clinical research demonstrates an association between polycystic ovary syndrome (PCOS) and endothelial dysfunction, a pathological state widely believed to be a hallmark of vascular disease; the underlying pathways, however, have not been defined. The purpose of this study was to characterize endothelial function in resistance arteries in a novel rat model of PCOS. Female rats were randomized at 3-4 wk to implantation of a 7.5-mg, 90-d dihydrotestosterone (DHT) pellet or a matched placebo. At 15-16 wk, experiments were performed on isolated mesenteric resistance arteries using a pressurized arteriograph. Endothelial function was assessed by the vasodilatory response of preconstricted arteries to acetylcholine (ACh) in the absence and presence of inhibitors for cyclooxygenase (indomethacin) and the thromboxane prostanoid receptor antagonist (SQ29,548). Distensibility was evaluated by measuring vessel diameter from 3-100 mm Hg, and elastin/collagen content was calculated on formalin-fixed vessels. Serum steroid levels were analyzed by sensitive RIA. DHT-induced PCOS rats were heavier, cycled irregularly, and had elevated blood pressure and smaller arterial lumens than controls. Furthermore, DHT vessels showed significantly reduced vasodilatory efficacy to ACh (with no change in sensitivity), reduced distensibility, and increased elastin content compared with controls. Within DHT animals, maximal dilation correlated negatively to DHT levels (r = -0.72) but not to body weight. Preincubation with either indomethacin or SC29,548 abrogated the dysfunction and restored full efficacy to ACh (P < 0.05). This is the first report to demonstrate the presence of 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.
Division of Reproductive Endocrinology and Infertility, University of Vermont, Burlington, Vermont 05401, USA. Jennifer.Keller@vtmednet.org
Jennifer
J
Keller
Maurizio
M
Mandala
Peter
P
Casson
George
G
Osol
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D042783:Endothelial Cells / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D011085:Polycystic Ovary Syndrome / Q000473:pathology*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents; D014664:Vasodilation / Q000187:drug effects
D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D013196:Dihydrotestosterone; D000109:Acetylcholine