Davis Lowell, Musso James, Soman Divya, Louey Samantha, Nelson Jonathan W, Jonker Sonnet S
Center for Developmental Health, Oregon Health & Science University , Portland, Oregon.
Department of Obstetrics and Gynecology, Oregon Health & Science University , Portland, Oregon.
Am J Physiol Regul Integr Comp Physiol. 2018 Sep 1;315(3):R500-R508. doi: 10.1152/ajpregu.00319.2017. Epub 2018 May 23.
Fetal anemia causes rapid and profound changes in cardiac structure and function, stimulating proliferation of the cardiac myocytes, expansion of the coronary vascular tree, and impairing early contraction and relaxation. Although hypoxia-inducible factor-1α is sure to play a role, adenosine, a metabolic byproduct that increases coronary flow and growth, is implicated as a major stimulus for these adaptations. We hypothesized that genes involved in myocardial adenosine signaling would be upregulated in chronically anemic fetuses and that calcium-handling genes would be downregulated. After sterile surgical instrumentation under anesthesia, gestationally timed fetal sheep were made anemic by isovolumetric hemorrhage for 1 wk (16% vs. 35% hematocrit). At 87% of gestation, necropsy was performed to collect heart tissue for PCR and immunohistochemical analysis. Anemia increased mRNA expression levels of adenosine receptors ADORA 1, ADORA2A, and ADORA2B in the left and right ventricles (adenosine receptor ADORA3 was unchanged). In both ventricles, anemia also increased expression of ectonucleoside triphosphate diphosphohydrolase 1 and ecto-5'-nucleotidase. The genes for both equilibrative nucleoside transporters 1 and 2 were expressed more abundantly in the anemic right ventricle but were not different in the left ventricle. Neither adenosine deaminase nor adenosine kinase cardiac levels were significantly changed by chronic fetal anemia. Chronic fetal anemia did not significantly change cardiac mRNA expression levels of the voltage-dependent L-type calcium channel, ryanodine receptor 1, sodium-calcium exchanger, sarcoplasmic/endoplasmic reticulum calcium transporting ATPase 2, phospholamban, or cardiac calsequestrin. These data support local metabolic integration of vascular and myocyte function through adenosine signaling in the anemic fetal heart.
胎儿贫血会导致心脏结构和功能迅速而深刻的变化，刺激心肌细胞增殖、冠状血管树扩张，并损害早期收缩和舒张功能。尽管缺氧诱导因子-1α肯定发挥了作用，但腺苷作为一种可增加冠状动脉血流量和促进生长的代谢副产物，被认为是这些适应性变化的主要刺激因素。我们假设，参与心肌腺苷信号传导的基因在慢性贫血胎儿中会上调，而钙处理基因会下调。在麻醉下进行无菌手术操作后，对处于特定妊娠阶段的胎羊通过等容性失血造成贫血1周（血细胞比容从35%降至16%）。在妊娠87%时，进行尸检以收集心脏组织用于PCR和免疫组织化学分析。贫血增加了左心室和右心室中腺苷受体ADORA 1、ADORA2A和ADORA2B的mRNA表达水平（腺苷受体ADORA3未发生变化）。在两个心室中，贫血还增加了外核苷酸三磷酸二磷酸水解酶1和外5'-核苷酸酶的表达。平衡核苷转运体1和2的基因在贫血的右心室中表达更为丰富，但在左心室中无差异。慢性胎儿贫血并未显著改变心脏中腺苷脱氨酶和腺苷激酶的水平。慢性胎儿贫血也未显著改变电压依赖性L型钙通道、兰尼碱受体1、钠钙交换体、肌浆网/内质网钙转运ATP酶2、受磷蛋白或心肌钙结合蛋白的心脏mRNA表达水平。这些数据支持了贫血胎儿心脏中通过腺苷信号传导实现血管和心肌细胞功能的局部代谢整合。
