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Adipocyte deficiency of ACE2 increases systolic blood pressures of obese female C57BL/6 mice.
Biology of Sex Differences ( IF 4.9 ) Pub Date : 2019-09-04 , DOI: 10.1186/s13293-019-0260-8
Robin Shoemaker 1 , Lisa R Tannock 2 , Wen Su 3 , Ming Gong 3 , Susan B Gurley 4 , Sean E Thatcher 5 , Frederique Yiannikouris 5 , Charles M Ensor 5 , Lisa A Cassis 5
Affiliation  

BACKGROUND Obesity increases the risk for hypertension in both sexes, but the prevalence of hypertension is lower in females than in males until menopause, despite a higher prevalence of obesity in females. We previously demonstrated that angiotensin-converting enzyme 2 (ACE2), which cleaves the vasoconstrictor, angiotensin II (AngII), to generate the vasodilator, angiotensin-(1-7) (Ang-(1-7)), contributes to sex differences in obesity-hypertension. ACE2 expression in adipose tissue was influenced by obesity in a sex-specific manner, with elevated ACE2 expression in obese female mice. Moreover, estrogen stimulated adipose ACE2 expression and reduced obesity-hypertension in females. In this study, we hypothesized that deficiency of adipocyte ACE2 contributes to obesity-hypertension of females. METHODS We generated a mouse model of adipocyte ACE2 deficiency. Male and female mice with adipocyte ACE2 deficiency or littermate controls were fed a low (LF) or a high fat (HF) diet for 16 weeks and blood pressure was quantified by radiotelemetry. HF-fed mice of each sex and genotype were challenged by an acute AngII injection, and blood pressure response was quantified. To translate these findings to humans, we performed a proof-of-principle study in obese transwomen in which systemic angiotensin peptides and blood pressure were quantified prior to and after 12 weeks of gender-affirming 17β-estradiol hormone therapy. RESULTS Adipocyte ACE2 deficiency had no effect on the development of obesity in either sex. HF feeding increased systolic blood pressures (SBP) of wild-type male and female mice compared to LF-fed controls. Adipocyte ACE2 deficiency augmented obesity-induced elevations in SBP in females, but not in males. Obese female, but not obese male mice with adipocyte ACE2 deficiency, had an augmented SBP response to acute AngII challenge. In humans, plasma 17β-estradiol concentrations increased in obese transwomen administered 17β-estradiol and correlated positively with plasma Ang-(1-7)/AngII balance, and negatively to SBP after 12 weeks of 17β-estradiol administration. CONCLUSIONS Adipocyte ACE2 protects female mice from obesity-hypertension, and reduces the blood pressure response to systemic AngII. In obese transwomen undergoing gender-affirming hormone therapy, 17β-estradiol administration may regulate blood pressure via the Ang-(1-7)/AngII balance.

中文翻译:

ACE2 的脂肪细胞缺乏会增加肥胖雌性 C57BL/6 小鼠的收缩压。

背景 肥胖会增加男女患高血压的风险,但在绝经前,女性的高血压患病率低于男性,尽管女性的肥胖患病率较高。我们之前已经证明,血管紧张素转换酶 2 (ACE2) 会切割血管收缩剂血管紧张素 II (AngII),从而产生血管扩张剂血管紧张素-(1-7) (Ang-(1-7)),从而导致性别差异在肥胖高血压。脂肪组织中 ACE2 的表达以性别特异性方式受到肥胖的影响,肥胖雌性小鼠中 ACE2 的表达升高。此外,雌激素刺激脂肪 ACE2 的表达并降低女性的肥胖高血压。在这项研究中,我们假设脂肪细胞 ACE2 的缺乏会导致女性肥胖高血压。方法 我们建立了一个脂肪细胞 ACE2 缺乏的小鼠模型。脂肪细胞 ACE2 缺乏或同窝对照的雄性和雌性小鼠被喂食低 (LF) 或高脂肪 (HF) 饮食 16 周,并通过无线电遥测法量化血压。每种性别和基因型的 HF 喂养小鼠都受到急性 AngII 注射的挑战,并量化了血压反应。为了将这些发现转化为人类,我们在肥胖的跨性别女性中进行了一项原理验证研究,其中在 12 周的性别确认 17β-雌二醇激素治疗之前和之后量化了全身血管紧张素肽和血压。结果 脂肪细胞 ACE2 缺乏对任何性别的肥胖发展都没有影响。与 LF 喂养的对照组相比,HF 喂养增加了野生型雄性和雌性小鼠的收缩压 (SBP)。脂肪细胞 ACE2 缺乏会增加肥胖引起的女性 SBP 升高,但在男性中则不然。脂肪细胞 ACE2 缺乏的肥胖雌性而非肥胖雄性小鼠对急性 AngII 挑战的 SBP 反应增强。在人类中,给予 17β-雌二醇的肥胖跨性别女性的血浆 17β-雌二醇浓度增加,并与血浆 Ang-(1-7)/AngII 平衡呈正相关,在 17β-雌二醇给药 12 周后与 SBP 呈负相关。结论 脂肪细胞 ACE2 保护雌性小鼠免于肥胖高血压,并降低对全身性 AngII 的血压反应。在接受性别确认激素治疗的肥胖跨性别女性中,17β-雌二醇给药可通过 Ang-(1-7)/AngII 平衡调节血压。但脂肪细胞 ACE2 缺乏的肥胖雄性小鼠对急性 AngII 挑战的 SBP 反应增强。在人类中,给予 17β-雌二醇的肥胖跨性别女性的血浆 17β-雌二醇浓度增加,并与血浆 Ang-(1-7)/AngII 平衡呈正相关,在 17β-雌二醇给药 12 周后与 SBP 呈负相关。结论 脂肪细胞 ACE2 保护雌性小鼠免于肥胖高血压,并降低对全身性 AngII 的血压反应。在接受性别确认激素治疗的肥胖跨性别女性中,17β-雌二醇给药可通过 Ang-(1-7)/AngII 平衡调节血压。但脂肪细胞 ACE2 缺乏的肥胖雄性小鼠对急性 AngII 挑战的 SBP 反应增强。在人类中,给予 17β-雌二醇的肥胖跨性别女性的血浆 17β-雌二醇浓度增加,并与血浆 Ang-(1-7)/AngII 平衡呈正相关,在 17β-雌二醇给药 12 周后与 SBP 呈负相关。结论 脂肪细胞 ACE2 保护雌性小鼠免于肥胖高血压,并降低对全身性 AngII 的血压反应。在接受性别确认激素治疗的肥胖跨性别女性中,17β-雌二醇给药可通过 Ang-(1-7)/AngII 平衡调节血压。给予 17β-雌二醇的肥胖变性妇女血浆 17β-雌二醇浓度增加,并与血浆 Ang-(1-7)/AngII 平衡呈正相关,在 17β-雌二醇给药 12 周后与 SBP 呈负相关。结论 脂肪细胞 ACE2 保护雌性小鼠免于肥胖高血压,并降低对全身性 AngII 的血压反应。在接受性别确认激素治疗的肥胖跨性别女性中,17β-雌二醇给药可通过 Ang-(1-7)/AngII 平衡调节血压。给予 17β-雌二醇的肥胖变性妇女血浆 17β-雌二醇浓度增加,并与血浆 Ang-(1-7)/AngII 平衡呈正相关,在 17β-雌二醇给药 12 周后与 SBP 呈负相关。结论 脂肪细胞 ACE2 保护雌性小鼠免于肥胖高血压,并降低对全身性 AngII 的血压反应。在接受性别确认激素治疗的肥胖跨性别女性中,17β-雌二醇给药可通过 Ang-(1-7)/AngII 平衡调节血压。
更新日期:2020-04-22
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