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

Influence of Constriction, Wall Tension, Smooth Muscle Activation and Cellular Deformation on Rat Resistance Artery Vasodilator Reactivity

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placental protein 13 pp13 induced vasodilation of resistance arteries from pregnant and nonpregnant rats occurs via endothelial signaling pathways

ABSTRACTPlacental protein 13 (PP13) induces hypotension in rats. This study aims to evaluate PP13 effects on isolated uterine arteries from nonpregnant and mid-pregnant rats. Vessels were isolated, cannulated, and pressurized to 50 mmHg within an arteriograph, preconstricted and exposed to increasing PP13 concentrations (10−13–10−8 M). PP13 elicited 38–50% arterial vasodilation with half-maximum response (EC50) = 1 pM. The relaxation was mediated by activating the endothelial-signaling pathways of prostaglandin and nitric oxide (NO). Accordingly, these results encourage evaluation of PP13 as a possible therapy for gestational diseases characterized by insufficient uteroplacental blood flow and/or maternal hypertension

Placental protein 13 (PP13) stimulates rat uterine vessels after slow subcutaneous administration.

To access publisher's full text version of this article click on the hyperlink belowReduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin. In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short- and long-term impact of PP13 on vessels' growth and size. The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days. In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vascu-lature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.European Union through ASPRE project Icelandic Research Fund (Rannis) Hananja eh

Differential Expression and Regulation of the Vascular Endothelial Growth Factor Receptors Neuropilin-1 and Neuropilin-2 in Rat Uterus 1

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