Turner Casey G, de Oliveira Karla, Lu Qing, Patel Ayan R, Pulakat Lakshmi, Jaffe Iris Z, DuPont Jennifer J
Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA 02111, USA.
Division of Cardiology, Department of Medicine, Tufts Medical Center, Boston, MA 02111, USA.
J Cardiovasc Aging. 2024 Jul;4(2). doi: 10.20517/jca.2024.09. Epub 2024 Aug 14.
Angiotensin II (AngII) affects cardiovascular health, mediating impacts through AngII type 1 (AT1R) and type 2 (AT2R) receptors. The present study investigated sex and aging-related differences in microvascular AngII receptor function in mice and humans.
Mesenteric resistance arteries (MRA) were isolated from 3-, 12-, and 18-month-old female and male C57/Bl6 mice. Wire myography was used to measure vasoconstriction to AngII and vasodilation to an AT2R agonist (compound 21, C21). Seven healthy adults (3 premenopausal women and 4 age-matched men) were recruited to participate in a study measuring cutaneous microvascular vasoconstriction to AngII in the presence and absence of 10 μM PD123319, an AT2R antagonist.
In murine MRA, AngII-induced constriction increases by 18 months in females and by 12 months in males. AT2R-mediated vasodilation was reduced with age in females only, which corresponds with a female-specific decrease in mesenteric AT2R mRNA expression. AT2R inhibition enhances AngII-induced constriction in young female, but not male, mice. Clinical data support that premenopausal women have attenuated AngII constriction . men, which is abrogated by AT2R inhibition. AT2R expression is greater in primary aortic smooth muscle cells, but not endothelial cells, from young women compared with men.
These data demonstrate enhanced microvascular AT2R function in young female mice and young women. There is a female-specific loss of AT2R function with age in mice, concomitant with declining AT2R expression. These findings implicate AT2R as a sex-specific target for microvascular dysfunction and aging-associated cardiovascular disease.
血管紧张素II（AngII）影响心血管健康，通过1型血管紧张素II受体（AT1R）和2型血管紧张素II受体（AT2R）介导其作用。本研究调查了小鼠和人类微血管AngII受体功能的性别差异及与衰老相关的差异。
从3个月、12个月和18个月大的雌性和雄性C57/Bl6小鼠中分离出肠系膜阻力动脉（MRA）。采用线式肌张力测定法测量对AngII的血管收缩反应以及对AT2R激动剂（化合物21，C21）的血管舒张反应。招募了7名健康成年人（3名绝经前女性和4名年龄匹配的男性）参与一项研究，该研究测量了在存在和不存在10μM AT2R拮抗剂PD123319的情况下皮肤微血管对AngII的血管收缩反应。
在小鼠MRA中，AngII诱导的收缩在雌性小鼠中18个月时增加，在雄性小鼠中12个月时增加。仅在雌性小鼠中，AT2R介导的血管舒张随年龄降低，这与肠系膜AT2R mRNA表达的雌性特异性降低相对应。AT2R抑制增强了年轻雌性小鼠而非雄性小鼠中AngII诱导的收缩。临床数据支持绝经前女性的AngII收缩减弱，男性则不然，而AT2R抑制可消除这种差异。与男性相比，年轻女性的原代主动脉平滑肌细胞而非内皮细胞中AT2R表达更高。
这些数据表明年轻雌性小鼠和年轻女性的微血管AT2R功能增强。在小鼠中，随着年龄增长，AT2R功能存在雌性特异性丧失，同时AT2R表达下降。这些发现表明AT2R是微血管功能障碍和衰老相关心血管疾病的性别特异性靶点。
