Maranon Rodrigo, Lima Roberta, Spradley Frank T, do Carmo Jussara M, Zhang Howei, Smith Andrew D, Bui Elizabeth, Thomas R Lucas, Moulana Mohadetheh, Hall John E, Granger Joey P, Reckelhoff Jane F
Department of Physiology and Biophysics, Women's Health Research Center.
Department of Physiology and Biophysics, Women's Health Research Center, Cardiovascular Renal Research Center, and.
Am J Physiol Regul Integr Comp Physiol. 2015 Apr 15;308(8):R708-13. doi: 10.1152/ajpregu.00411.2014. Epub 2015 Feb 18.
Women with polycystic ovary syndrome (PCOS) have hyperandrogenemia and increased prevalence of risk factors for cardiovascular disease, including elevated blood pressure. We recently characterized a hyperandrogenemic female rat (HAF) model of PCOS [chronic dihydrotestosterone (DHT) beginning at 4 wk of age] that exhibits similar characteristics as women with PCOS. In the present studies we tested the hypotheses that the elevated blood pressure in HAF rats is mediated in part by sympathetic activation, renal nerves, and melanocortin-4 receptor (MC4R) activation. Adrenergic blockade with terazosin and propranolol or renal denervation reduced mean arterial pressure (MAP by telemetry) in HAF rats but not controls. Hypothalamic MC4R expression was higher in HAF rats than controls, and central nervous system MC4R antagonism with SHU-9119 (1 nmol/h icv) reduced MAP in HAF rats. Taking a genetic approach, MC4R null and wild-type (WT) female rats were treated with DHT or placebo from 5 to 16 wk of age. MC4R null rats were obese and had higher MAP than WT control rats, and while DHT increased MAP in WT controls, DHT failed to further increase MAP in MC4R null rats. These data suggest that increases in MAP with chronic hyperandrogenemia in female rats are due, in part, to activation of the sympathetic nervous system, renal nerves, and MC4R and may provide novel insights into the mechanisms responsible for hypertension in women with hyperandrogenemia such as PCOS.
患有多囊卵巢综合征（PCOS）的女性存在高雄激素血症，心血管疾病风险因素的患病率增加，包括血压升高。我们最近建立了一种PCOS的高雄激素血症雌性大鼠（HAF）模型[从4周龄开始长期给予二氢睾酮（DHT）]，该模型表现出与患有PCOS的女性相似的特征。在本研究中，我们检验了以下假设：HAF大鼠血压升高部分是由交感神经激活、肾神经和黑皮质素-4受体（MC4R）激活介导的。用特拉唑嗪和普萘洛尔进行肾上腺素能阻断或肾去神经支配可降低HAF大鼠的平均动脉压（通过遥测），但对对照组无效。HAF大鼠下丘脑MC4R表达高于对照组，用SHU-9119（1 nmol/h，脑室内注射）进行中枢神经系统MC4R拮抗可降低HAF大鼠的平均动脉压。采用基因方法，从5至16周龄对MC4R基因敲除和野生型（WT）雌性大鼠给予DHT或安慰剂。MC4R基因敲除大鼠肥胖，平均动脉压高于WT对照大鼠，虽然DHT可使WT对照大鼠的平均动脉压升高，但DHT未能使MC4R基因敲除大鼠的平均动脉压进一步升高。这些数据表明，雌性大鼠慢性高雄激素血症导致的平均动脉压升高部分归因于交感神经系统、肾神经和MC4R的激活，这可能为患有高雄激素血症（如PCOS）的女性高血压发病机制提供新的见解。
