Javeshghani Danesh, Sairam M Ram, Neves Mario Fritsch, Schiffrin Ernesto L, Touyz Rhian M
CIHR Multidisciplinary Research Group on Hypertension, Canada.
J Hypertens. 2006 Jul;24(7):1365-73. doi: 10.1097/01.hjh.0000234117.25401.f8.
Follitropin-receptor knockout (FORKO) mice are estrogen-deficient, hyperandrogenic and exhibit features of menopause and elevated blood pressure (BP). Because the renin-angiotensin system has been implicated in menopause-associated hypertension, we questioned whether angiotensin II (Ang II) challenge would further increase BP in FORKO mice and whether this is associated with cardiovascular remodeling and inflammation.
Ang II (400 ng/kg per min) increased BP, assessed by radiotelemetry, similarly in female FORKO and wild-type (WT) mice. Acetylcholine-induced vasodilation was attenuated and Ang II-induced contraction was enhanced in FORKO mice (P < 0.05). This was associated with increased expression of vascular Ang type 1 receptors (AT1R) and estrogen receptor alpha (ERalpha). Vascular structure (media/lumen ratio) was similar in both groups. Abundance of gp91, nitrotyrosine formation and superoxide production, indices of inflammation and cardiac collagen content were increased in Ang II-treated FORKO compared to Ang II-treated WT mice (P < 0.05).
Thus, in FORKO mice Ang II exacerbates endothelial dysfunction, augments contractility, increases oxidative stress, and promotes cardiac fibrosis without worsening vascular remodeling or BP elevation compared to Ang II-treated WT controls. Our findings suggest that in FORKO mice Ang II may be more important in influencing vascular tone and endothelial function, possibly through oxidative stress and altered ERalpha signaling, than in arterial remodeling and BP elevation.
促卵泡激素受体敲除（FORKO）小鼠雌激素缺乏、雄激素过多，表现出更年期特征和血压（BP）升高。由于肾素-血管紧张素系统与更年期相关高血压有关，我们质疑血管紧张素II（Ang II）刺激是否会使FORKO小鼠的血压进一步升高，以及这是否与心血管重塑和炎症有关。
通过无线电遥测评估，Ang II（400 ng/kg每分钟）使雌性FORKO小鼠和野生型（WT）小鼠的血压升高程度相似。乙酰胆碱诱导的血管舒张在FORKO小鼠中减弱，而Ang II诱导的收缩增强（P < 0.05）。这与血管1型Ang受体（AT1R）和雌激素受体α（ERα）的表达增加有关。两组的血管结构（中膜/管腔比值）相似。与Ang II处理的WT小鼠相比，Ang II处理的FORKO小鼠中炎症指标gp91的丰度、硝基酪氨酸形成和超氧化物产生以及心脏胶原含量增加（P < 0.05）。
因此，在FORKO小鼠中，与Ang II处理的WT对照相比，Ang II加剧了内皮功能障碍，增强了收缩性，增加了氧化应激，并促进了心脏纤维化，但没有使血管重塑恶化或血压升高。我们的研究结果表明，在FORKO小鼠中，Ang II可能在影响血管张力和内皮功能方面比在动脉重塑和血压升高中更重要，可能是通过氧化应激和改变的ERα信号传导实现的。
