Hesson Ashley M, Sangtani Ajleeta, Bergin Ingrid L, Langen Elizabeth, Hunker Kristina, Kumar Nitin, Ganesh Santhi K
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI.
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI.
Am J Obstet Gynecol. 2025 Mar 29. doi: 10.1016/j.ajog.2025.03.035.
Hypertensive disorders of pregnancy are important risk factors for later-life cardiovascular diseases. SGLT2 (sodium-glucose cotransporter-2) inhibition improves outcomes in heart failure, a later-life risk that disproportionately affects those with preeclampsia superimposed on chronic hypertension. SGLT2 inhibition during pregnancy and the postpartum period has not been effectively modeled or tested in superimposed preeclampsia as a potential cardiovascular risk-reducing intervention.
This study aimed to (1) confirm the phenotype of superimposed preeclampsia in the BPH/2J mouse model, (2) test the short- and long-term obstetrical and cardiovascular effects of administering an SGLT2 inhibitor (dapagliflozin) in pregnancy and the immediate postpartum period in this model, and (3) identify molecular effects of SGLT2 inhibition in cardiovascular tissues during and after a treated pregnancy.
We established the BPH/2J model of superimposed preeclampsia and then randomly assigned pregnant BPH/2J mice with implanted telemetry devices to dapagliflozin-enriched chow or control chow starting early in gestation through 21 days after delivery. Maternal cardiovascular and obstetrical outcomes including circulating plasma protein markers, urine studies, obstetrical ultrasounds, and tissue histopathology were compared between the groups. Hearts and aortae were analyzed using serial echocardiography and spatial transcriptomics in late gestation or at 6 months postpartum.
BPH/2J mice had baseline chronic hypertension that worsened in pregnancy with the development of proteinuria and elevated plasma sFlt-1 levels, consistent with superimposed preeclampsia. Mid-gestation systolic blood pressures were higher in the untreated group than the dapagliflozin-treated group (+2.87 mm Hg; P<.001). There were no differences in the number of pups or estimated fetal pup weights between the groups, whereas amniotic fluid volume, placental size, and markers of placental perfusion were improved in the dapagliflozin-treated group. The untreated group had higher aortic peak velocities in late pregnancy compared with the dapagliflozin-treated group (748.1 vs 561.9 mm/s; P=.004×10). One maternal death occurred in the untreated group, with no events in the dapagliflozin-treated group. In late life, the untreated group had significant loss of left ventricular function relative to their prepregnancy baseline, whereas dapagliflozin-treated mice had relatively preserved left ventricular function (-20.0% vs -7.6% change; P=.004×10; 49.0%±6.34% untreated-baseline to 30.5%±6.78% untreated-aged; 44.9%±8.63% treated-baseline to 36.5%±6.39% treated-aged). Tissue transcriptomic analyses and Masson's trichrome staining demonstrated attenuation of cardiac fibrosis and extracellular remodeling processes with SGLT2 inhibition.
In a murine model of superimposed preeclampsia, dapagliflozin treatment during pregnancy and the puerperium improved physiological cardiovascular parameters during gestation and cardiac function later in life. This may be related to observed molecular effects of SGLT2 inhibition treatment, particularly its antifibrotic and metabolic actions associated with reduced markers of fibrotic pathologic remodeling in treated BPH/2Js during and after pregnancy.
妊娠高血压疾病是日后发生心血管疾病的重要危险因素。钠-葡萄糖协同转运蛋白2（SGLT2）抑制作用可改善心力衰竭的预后，而心力衰竭是一种日后发生的风险，对患有慢性高血压并发子痫前期的患者影响尤为严重。在慢性高血压并发子痫前期患者中，孕期及产后抑制SGLT2作为一种潜在的降低心血管风险的干预措施，尚未得到有效模拟或测试。
本研究旨在（1）在BPH/2J小鼠模型中确认慢性高血压并发子痫前期的表型，（2）测试在该模型中孕期及产后立即给予SGLT2抑制剂（达格列净）的短期和长期产科及心血管效应，（3）确定孕期治疗期间及之后SGLT2抑制作用对心血管组织的分子效应。
我们建立了慢性高血压并发子痫前期的BPH/2J模型，然后将植入遥测装置的怀孕BPH/2J小鼠从妊娠早期开始随机分为富含达格列净的饲料组或对照组，直至产后21天。比较两组的母体心血管和产科结局，包括循环血浆蛋白标志物、尿液研究、产科超声检查和组织病理学检查。在妊娠晚期或产后6个月，使用连续超声心动图和空间转录组学分析心脏和主动脉。
BPH/2J小鼠有基线慢性高血压，孕期随着蛋白尿的出现和血浆可溶性血管内皮生长因子受体1（sFlt-1）水平升高而加重，符合慢性高血压并发子痫前期。未治疗组妊娠中期收缩压高于达格列净治疗组（高2.87 mmHg；P<0.001）。两组之间的幼崽数量或估计的胎儿体重无差异，而达格列净治疗组的羊水量、胎盘大小和胎盘灌注标志物有所改善。与达格列净治疗组相比，未治疗组妊娠晚期主动脉峰值速度更高（748.1对561.9 mm/s；P=0.004×10）。未治疗组发生1例母体死亡，达格列净治疗组无事件发生。在晚年，未治疗组相对于孕前基线左心室功能显著丧失，而达格列净治疗的小鼠左心室功能相对保留（变化-20.0%对-7.6%；P=0.004×10；未治疗组基线49.0%±6.34%至未治疗组老年30.5%±6.78%；治疗组基线44.9%±8.63%至治疗组老年36.5%±6.39%）。组织转录组分析和Masson三色染色显示，SGLT2抑制可减轻心脏纤维化和细胞外重塑过程。
在慢性高血压并发子痫前期的小鼠模型中，孕期及产褥期给予达格列净治疗可改善孕期生理心血管参数及晚年心脏功能。这可能与观察到的SGLT2抑制治疗的分子效应有关，特别是其抗纤维化和代谢作用，与孕期及产后治疗的BPH/2J小鼠纤维化病理重塑标志物减少有关。
