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Effects of estradiol on transcriptional profiles in atherosclerotic iliac arteries in ovariectomized cynomolgus macaques

Eyster, Kathleen M. PhD1; Appt, Susan DVM2; Chalpe, Abha PhD1; Mark-Kappeler, Connie J. PhD1; Register, Thomas C. PhD2; Clarkson, Thomas B. DVM2

doi: 10.1097/GME.0b013e31829367c0
Original Articles

Objective: This study aimed to assess the in vivo effects of estradiol treatment on arterial gene expression in atherosclerotic postmenopausal female monkeys.

Methods: Eight ovariectomized cynomolgus monkeys were fed atherogenic diets for 6.5 years. The left iliac artery was biopsied before randomization to the estradiol group (human equivalent dose of 1 mg/d, n = 4) or the vehicle group (n = 4) for 8 months. The right iliac artery was obtained at necropsy. Transcriptional profiles in pretreatment versus posttreatment iliac arteries were compared to assess the responses of atherosclerotic arteries to estradiol.

Results: Iliac artery plaque size did not differ between the estradiol group and the placebo group at baseline or during the treatment period. Nevertheless, estradiol treatment was associated with increased expression of 106 genes and decreased expression of 26 genes in the iliac arteries. Estradiol treatment increased the expression of extracellular matrix genes, including the α1 chain of type I collagen, the α2 chain of type VI collagen, and fibulin 2, suggestive of an increase in the proportion or phenotype of smooth muscles or fibroblasts in lesions. Also increased were components of the insulin-like growth factor pathway (insulin-like growth factor 1, insulin-like growth factor binding protein 4, and insulin-like growth factor binding protein 5) and the Wnt signaling pathway (secreted frizzled-related protein 2, secreted frizzled-related protein 4, low-density lipoprotein receptor–related protein 6, and Wnt1-inducible signaling pathway protein 2).

Conclusions: Estradiol treatment of monkeys with established atherosclerosis affected iliac artery gene expression, suggesting changes in the cellular composition of lesions. Moreover, it is probable that the presence of atherosclerotic plaque affected the gene expression responses of arteries to estrogen.

From the 1Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, Vermillion, SD; and 2Department of Pathology (Comparative Medicine), Wake Forest University School of Medicine, Winston-Salem, NC.

Received January 8, 2013; revised and accepted March 18, 2013.

Funding/support: This work was supported by grants PO1 HL45666 (T.B.C.), RO1 AG28641 (T.C.R.), and RO1 AG27847 (S.A.). DNA microarray and real-time reverse transcription–polymerase chain reaction experiments were carried out at the Genomics Core facility of the University of South Dakota, which was supported by National Institutes of Health grant INBRE 2 P20 RR016479.

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Kathleen M. Eyster, PhD, Division of Basic Biomedical Sciences, Sanford School of Medicine of the University of South Dakota, 414 East Clark Street, Vermillion, SD 57069. E-mail: Kathleen.Eyster@usd.edu

© 2014 by The North American Menopause Society.