School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW, Australia.
Biol Sex Differ. 2021 Apr 20;12(1):31. doi: 10.1186/s13293-021-00376-1.
Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia.
The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling.
The RUPP procedure induced significant increases in blood pressure (p < 0.001), collagen deposition (p < 0.001) and cardiac BNP45 (p < 0.05). It also induced a significant increase in cardiac FKBPL mRNA (p < 0.05) and protein expression (p < 0.01). RUPP placentae also exhibited increased collagen deposition and decreased Flt1 mRNA expression (p < 0.05). RUPP kidneys revealed an increase in average glomerular size (p < 0.05). Cardiac spheroids showed a significant increase in FKBPL expression when treated with LOPE plasma (p < 0.05) and a trend towards increased FKBPL expression following treatment with EOPE plasma (p = 0.06).
The rat RUPP model induced cardiac, renal and placental features reflective of preeclampsia. FKBPL was increased in the hearts of RUPP rats and cardiac spheroids treated with plasma from women with preeclampsia, perhaps reflective of restricted angiogenesis and inflammation in this disorder. Elucidation of these novel FKBPL mechanisms in cardiac health in preeclampsia could be key in preventing future CVD.
子痫前期是一种妊娠期间的心血管疾病，会增加未来心血管和代谢疾病的风险。子痫前期中心脏健康的发病机制和涉及的机制有很多尚不清楚。一种新的抗血管生成蛋白 FKBPL 似乎在子痫前期和心血管疾病 (CVD) 中都具有潜在作用。因此，在这项研究中，我们旨在研究大鼠减少子宫灌注压 (RUPP) 和子痫前期的 3D 心脏球体模型中的心脏健康和 FKBPL 调节。
在怀孕的大鼠中诱导 RUPP 模型，并对心脏、肾脏、肝脏和胎盘进行组织学分析（n = 6）。进行苦味酸天狼星红染色，以定量大鼠心脏、胎盘和肝脏中 I 型和 III 型胶原的沉积，作为纤维化的指标。使用 RT-qPCR 确定心脏和/或胎盘中小鼠 Fkbpl、Icam1、Vcam1、Flt1 和 Vegfa mRNA 的变化，以及 ELISA 评估心脏脑利钠肽 (BNP45) 和 FKBPL 的分泌。还进行了免疫荧光染色以分析心脏 FKBPL 的表达。使用人心肌成纤维细胞和人冠状动脉内皮细胞生成心脏球体，并用人正常血压对照者、早发型子痫前期 (EOPE) 和晚发型子痫前期 (LOPE) 的患者血浆处理；n = 3。通过免疫荧光标记定量 FKBPL 和 CD31 的表达。
RUPP 程序导致血压显著升高（p < 0.001）、胶原沉积显著增加（p < 0.001）和心脏 BNP45 显著增加（p < 0.05）。它还导致心脏 FKBPL mRNA 表达显著增加（p < 0.05）和蛋白表达显著增加（p < 0.01）。RUPP 胎盘也表现出胶原沉积增加和 Flt1 mRNA 表达减少（p < 0.05）。RUPP 肾脏显示平均肾小球大小增加（p < 0.05）。用 LOPE 血浆处理心脏球体后，FKBPL 表达显著增加（p < 0.05），用 EOPE 血浆处理后 FKBPL 表达有增加的趋势（p = 0.06）。
RUPP 大鼠模型诱导出与子痫前期相似的心脏、肾脏和胎盘特征。在 RUPP 大鼠的心脏和接受子痫前期患者血浆处理的心脏球体中，FKBPL 增加，这可能反映了该疾病中血管生成和炎症受限。阐明子痫前期中心脏健康的这些新的 FKBPL 机制可能是预防未来 CVD 的关键。
