子痫前期后ATR信号传导降低导致内皮功能障碍。
Reduced ATR Signaling Contributes to Endothelial Dysfunction After Preeclampsia.
作者信息
Schwartz Kelsey S, Sun Mingyao, Jalal Diana I, Santillan Mark K, Stanhewicz Anna E
机构信息
Department of Health and Human Physiology, The University of Iowa (K.S.S., A.E.S.).
Department of Internal Medicine (M.S., D.I.J.), Carver College of Medicine, Iowa City, IA.
出版信息
Hypertension. 2025 May;82(5):904-913. doi: 10.1161/HYPERTENSIONAHA.124.24098. Epub 2024 Dec 26.
BACKGROUND
Women who had preeclampsia (a history of preeclampsia) have a >4-fold risk of developing cardiovascular disease compared with women who had an uncomplicated pregnancy (history of healthy pregnancy). Despite the remission of clinical symptoms after pregnancy, vascular endothelial dysfunction persists postpartum, mediated in part by exaggerated Ang II (angiotensin II)-mediated constriction. However, the role of vasodilatory ATRs (Ang II type 2 receptors) in this dysfunction is unknown. We examined the functional role of ATR in the microvasculature postpartum and whether acute activation of ATR improves microvascular endothelial function after preeclampsia.
METHODS
Overall, 24 women (n=12/group) participated. We measured cutaneous vascular conductance responses to (1) graded infusion of compound 21 (ATR agonist; 10-10M) alone or with NG-nitro-l-arginine methyl ester (NO synthase inhibitor; 15 mM) and (2) a standardized local heating protocol in control and 10M compound 21-treated sites. Expression of Ang II receptor subtypes I and II in biopsied venous endothelial cells was quantified using immunofluorescence.
RESULTS
ATR-mediated dilation (<0.01) and the NO-dependent contribution (=0.003) of this response were reduced in women with a history of preeclampsia. Endothelial ATR expression was lower in women with a history of preeclampsia (<0.01), but there were no differences in endothelial ATR (Ang II type 1 receptor) expression (>0.05). Acute activation of ATR during local heating improved endothelium (<0.01) and NO-dependent (<0.01) dilation in women with a history of preeclampsia but had no effect in women with a history of healthy pregnancy (both >0.05).
CONCLUSIONS
Reductions in ATR-mediated dilation contribute to attenuated or impaired endothelial function in women who had a pregnancy complicated by preeclampsia. Furthermore, ATR activation may improve endothelial function through NO-dependent mechanisms in otherwise healthy women who had preeclampsia before the onset of cardiovascular disease.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT05937841.
背景
与孕期正常（健康妊娠史）的女性相比，患有子痫前期（子痫前期病史）的女性患心血管疾病的风险高出4倍多。尽管孕期后临床症状有所缓解，但产后血管内皮功能障碍仍然存在，部分原因是血管紧张素II（Ang II）介导的血管收缩反应过度。然而，血管舒张性血管紧张素II受体（2型血管紧张素II受体）在这种功能障碍中的作用尚不清楚。我们研究了产后微血管中血管紧张素II受体（ATR）的功能作用，以及子痫前期后急性激活ATR是否能改善微血管内皮功能。
方法
总共24名女性（每组12名）参与了研究。我们测量了皮肤血管传导反应，包括：（1）单独静脉输注化合物21（ATR激动剂；10 - 10M）或与NG - 硝基 - L - 精氨酸甲酯（一氧化氮合酶抑制剂；15 mM）联合输注时的反应，以及（2）在对照部位和用10M化合物21处理的部位进行标准化局部加热方案后的反应。使用免疫荧光法定量分析活检静脉内皮细胞中血管紧张素II受体I型和II型的表达。
结果
有子痫前期病史的女性中，ATR介导的血管舒张反应（<0.01）及其一氧化氮依赖性反应贡献（=0.003）降低。有子痫前期病史的女性内皮细胞ATR表达较低（<0.01），但内皮细胞血管紧张素II 1型受体（ATR）表达无差异（>0.05）。局部加热期间急性激活ATR可改善有子痫前期病史女性的内皮功能（<0.01）和一氧化氮依赖性血管舒张功能（<0.01），但对有健康妊娠史的女性无影响（两者均>0.05）。
结论
ATR介导的血管舒张功能降低导致子痫前期合并妊娠女性的内皮功能减弱或受损。此外，在心血管疾病发病前曾患子痫前期的其他健康女性中，激活ATR可能通过一氧化氮依赖性机制改善内皮功能。
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