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8 May 2017 Hyperandrogenemia reduces endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric artery of female rats
Jay S. Mishra, Amar S. More, Gary D. V. Hankins, Sathish Kumar
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Abstract

Women with polycystic ovary syndrome (PCOS) are often presented with hyperandrogenemia along with vascular dysfunction and elevated blood pressure. In animal models of PCOS, antiandrogen treatment decreased blood pressure, indicating a key role for androgens in the development of hypertension. However, the underlying androgen-mediated mechanism that contributes to increased blood pressure is not known. This study determined whether elevated androgens affect endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular relaxation responses through alteration in function of gap junctional proteins. Female rats were implanted with placebo or dihydrotestosterone (DHT) pellets (7.5 mg, 90-day release). After 12 weeks of DHT exposure, blood pressure was assessed through carotid arterial catheter and endothelium-dependent mesenteric arterial EDHF relaxation using wire myograph. Connexin expression in mesenteric arteries was also examined. Elevated DHT significantly increased mean arterial pressure and decreased endothelium-dependent EDHF-mediated acetylcholine relaxation. Inhibition of Cx40 did not have any effect, while inhibition of Cx37 decreased EDHF relaxation to a similar magnitude in both controls and DHT females. On the other hand, inhibition of Cx43 significantly attenuated EDHF relaxation in mesenteric arteries of controls but not DHT females. Elevated DHT did not alter Cx37 or Cx40, but decreased Cx43 mRNA and protein levels in mesenteric arteries. In vitro exposure of DHT to cultured mesenteric artery smooth muscle cells dose-dependently downregulated Cx43 expression. In conclusion, increased blood pressure in hyperandrogenic females is due, at least in part, to decreased EDHF-mediated vascular relaxation responses. Decreased Cx43 expression and activity may play a role in contributing to androgen-induced decrease in EDHF function.

Summary Sentence

Hyperandrogenism in female rats reduced EDHF function via decrease in connexin 43 expression and activity in mesenteric arteries, providing a molecular mechanism linking elevated androgens and increased blood pressure.

© The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Jay S. Mishra, Amar S. More, Gary D. V. Hankins, and Sathish Kumar "Hyperandrogenemia reduces endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric artery of female rats," Biology of Reproduction 96(6), 1221-1230, (8 May 2017). https://doi.org/10.1093/biolre/iox043
Received: 17 January 2017; Accepted: 8 May 2017; Published: 8 May 2017
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