Natural killer cells in mouse pregnancy and in circulatory regulation

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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.