Natural killer cells in mouse pregnancy and in circulatory regulation

主要的心血管适应在健康的怀孕期间发生得很快。我们发现在NK-T-B-和NK+T-B-小鼠中怀孕会导致母体心脏结构和功能的异常。子宫动脉、胎盘和胎儿循环参数的异常也被发现，这导致了我们的假设，即NK细胞和T细胞在怀孕期间参与了循环调节。NK和T细胞表达肾素-血管紧张素系统的所有成员，肾素-血管紧张素系统是动脉血压的主要长期控制因素。在4个具体目标中提出了针对性别和怀孕时间进程的研究，以解决淋巴细胞的血流动力学行为及其调节。这项研究具有全球意义，因为大约15%的孕妇有异常的心血管问题，但我们缺乏对无处不在的淋巴细胞对体内平衡的贡献的见解。我们有一个同源小鼠小组(NK+T+B+；NK-T+B+；NK+T-B-和NK-T-B-)，并掌握了放射遥测和显微超声，使这些研究成为可能，我们的初步工作表明，淋巴细胞在母体和胎儿心脏上的结构和功能作用。在目标1中，将通过连续放射遥测比较饮食和药物对4种基因型的男性和非孕女性的升压反应，以寻求NK细胞对血流动力学的调节作用。在目标2中，将使用放射遥测、显微超声和组织形态计量学来确定NK细胞在NK-T+B+小鼠怀孕期间在循环结构和功能中的作用。这一目标还将询问受孕或母亲是否在血压中形成正常的妊娠变化，以及通过什么机制。在目标3中，将寻求在螺旋动脉(SA)血管系统中定位新描述的两个Unk细胞亚群并触发Unk细胞合成干扰素γ(IFNG)的机制。在目标4中，将确定Unk细胞来源的IFNG针对基质细胞(3个SA相关细胞系)的基因，以开发Unk细胞触发的SA修饰步骤的集成模型。从这些研究中获得的信息将有助于理解NK细胞和T细胞如何促进循环内稳态，以及它们的功能是否包括正常心血管反应的妊娠编程。

Major cardiovascular adaptations occur rapidly in healthy pregnancy. We found that pregnancy in NK-T-B- and NK+T-B- mice induces abnormal maternal heart structure and function. Anomalous uterine arterial, placental and fetal circulatory parameters were also found, leading to our postulate that NK cells and T cells contribute to circulatory regulation during pregnancy. NK and T cells express all members of the renin-angiotensin system, the major long term controller of arterial pressure (BP). Sex-specific and pregnancy time-course studies are proposed in 4 specific Aims to address the hemodynamic actions of lymphocytes and their regulation. This research is globally significant since ~15% of pregnancies have abnormal cardiovascular issues yet we lack insight to homeostatic contributions from ubiquitous lymphocytes. We have a congenic mouse panel (NK+T+B+; NK-T+B+; NK+T-B- and NK-T-B-) and mastery of radiotelemetry and micro-ultrasound to enable these studies and our preliminary work suggests structural and functional roles for lymphocytes on maternal and fetal hearts. In Aim 1, hemodynamic regulatory contributions of NK cells will be sought by comparing diet and drug induced pressor responses in males and non pregnant females of the 4 genotypes by continuous radiotelemetry. In Aim 2, NK cell roles in circulatory structure and function will be defined across pregnancy in NK-T+B+ mice using radiotelemetry, micro-ultrasound and histomorphometry. This aim will also ask if the conceptus or the mother patterns normal gestational shifts in BP and by what mechanisms. In Aim 3, mechanisms that position the 2 newly described uNK cell subsets within the spiral arterial (SA) vasculature and trigger interferon gamma (Ifng) synthesis by uNK cells will be sought. In Aim 4, genes targeted in stromal cells (3 SA-associated cell lineages) by uNK cell-derived Ifng will be identified to develop an integrated model of uNK cell-triggered steps in SA modification. Information gained from these studies will be valuable in understanding how NK cells and T cells contribute to circulatory homeostasis and if their functions include gestational programming of normal cardiovascular responses.