Analysis of the vascular responses in a murine model of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of the reproductive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 mg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significant decrease in acetylcholine-induced aortic relaxations, with no change in calcitonin generelated peptide-or sodium nitroprusside-induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT-exposed mice, hyperandrogenemia specifically decreases endotheliumdependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients.

Cardiac Nitric Oxide Synthases and Na+/K+-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone

“…Evidences reported by Elia et al (Elia et al, 2006), obtained after dehydroepiandrosterone treatment of prepubertal BALBc/mice, point to the diminished ovarian eNOS activity and increased ovarian protein expression of iNOS. However, in contrast to the results of the present and other mentioned studies, no differences were seen in the total expression level of eNOS and the eNOS Ser 1177 phosphorylation level in the lungs of C57BL/6 J mice after DHT treatment (Labruijere et al, 2013). Studies reporting status of Na + /K + -ATPase in insulin resistance are scanty.…”

“…Alpha 1 isoform is ubiquitously distributed, while α2 subunit is characteristic of muscle, heart and fat tissues, insulin-regulated and has a specific role in Ca 2 + signaling during cardiac contraction (Sweeney and Klip, 1998). Data on NO production and NOSs activity in PCOS are quite controversial (Labruijere et al, 2013;Paradisi et al, 2001), while evidences on NOSs and Na + /K + -ATPase function in heart of females with PCOS are completely missing. Insulin regulates eNOS phosphorylation/activity (Yu et al, 2011) and plasma membrane level of subunits of Na + /K + -ATPase (Comellas et al, 2010).…”

Carotid Intima-Media Thickness Is Associated with Increased Androgens in Adolescents and Young Adults with Classical Congenital Adrenal Hyperplasia

“…Androgens have been shown to have both direct and indirect effects on CVD risk, interacting with the vascular endothelium to promote inflammation and oxidative stress [31], and indirectly increasing blood pressure via actions on the kidney [30]. Possible mechanisms can be derived from rodent models, where testosterone increases the production of reactive oxygen species via activation of cytosolic NADPH-oxidase subunit p47phox, reversing the protective effects of estrogen on vascular function in post-menopausal animals [32], and reduces endothelium-dependent vasorelaxation in a PCOS model [33]. Although CVD risk in PCOS has been more extensively studied compared to CAH, the CAH model includes both sexes.…”

Rodent Models of Polycystic Ovary Syndrome: Phenotypic Presentation, Pathophysiology, and the Effects of Different Interventions

“…However, in DHT-induced PCOS in rats and mice hyperandrogenemia specifically impairs vascular function, alters markers of vascular endothelial function, and decreases endothelium-dependent vasorelaxation together with an elevated blood pressure. 31,69 In addition, EV-induced PCOS rats have significantly higher mean systolic blood pressure than controls. 25…”