Ly49 receptors activate angiogenic mouse DBA＋ uterine natural killer cells

In humans, specific patterns of killer immunoglobulin-like receptors （KIRs） expressed by uterine natural killer （uNK） cells are linked through HLA-C with pregnancy complications （infertility, recurrent spontaneous abortion, intrauterine growth restriction and preeclampsia）. To identify mechanisms underpinning the associations between NK cell activation and pregnancy success, pregnancies were studied in mice with genetic knockdown （KD） of the MHC-activated Ly49 receptor gene family. B6.Ly49KD pregnancies were compared to normal control B6.Ly49z29 and C57BL/6 （B6） pregnancies. At mid-pregnancy （gestation day （gd9.5））, overall uNK cell （TCRI^-CD122＋DBA＋DX5- （DBA＋DX5-）） and TCRIβ-CD122＋DBA-DX5＋ （DBA-DX5＋）） frequencies in pregnant uterus were similar between genotypes. Ly49KD lowered the normal frequencies of Ly49＋ uNK cells from 90.3% to 47.8% in DBA-DX5＋ and 78.8% to 6.3% in DBA＋DX5- uNK cell subtypes. B6.Ly49KD matings frequently resulted in expanded blastocysts that did not implant （subfertility）. B6.Ly49KD mice that established pregnancy had gestational lengths and litter sizes similar to controls. B6.Ly49KD neonates, however, were heavier than controls. B6.Ly49KD implantation sites lagged in early （gd6.5） decidual angiogenesis and were deficient in mid-pregnancy （gd 10.5） spiral arterial remodelling. Ultrastructural analyses revealed that B6.Ly49KD uNK cells had impaired granulogenesis, while immunocytochemistry revealed deficient vascular endothelial cell growth factor （VEGFA） production. Perforin and IFNG expression were normal in B6.Ly49KD uNK cells. Thus, in normal mouse pregnancies, Ly49 receptor signaling must promote implantation, early decidual angiogenesis and mid-pregnancy vascular remodelling. Disturbances in these functions may underlie the reported genetic associations between human pregnancy complications and the inability of specific conceptus MHCs to engage activating KIR on uNK cells.

Natural killer cell-triggered vascular transformation:maternal care before birth?

Natural killer(NK)cells are found in lymphoid and non-lymphoid organs.In addition to important roles in immune surveillance,some NK cells contribute to angiogenesis and circulatory regulation.The uterus of early pregnancy is a non-lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites.In species with invasive hemochorial placentation,these uterine natural killer(uNK)cells,via secretion of cytokines,chemokines,mucins,enzymes and angiogenic growth factors,contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis.In humans,uNK cells have the phenotype CD56^(bright) CD16^(dim) and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy.Gene expression studies indicate that CD56^(bright) CD16^(dim) uterine and circulating cells are functionally distinct.In humans but not mice or other species with post-implantation decidualization,uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility.Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function,achieved via interferon(IFN)-c secretion.During spiral arterial modification,branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict.The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance,high-volume channels.Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women.Here we briefly review key information concerning uNK cell functions from studies in rodents,summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized,pregnant mouse model for in vivo investigations of human uNK cell functions.

Leukocyte driven-decidual angiogenesis in early.pregnancy

Successful pregnancy and long-term, post-natal maternal and offspring cardiac, vascular and metabolic health require key maternal cardiovascular adaptations over gestation. Within the pregnant decidualizing uterus, coordinated vascular, immunological and stromal cell changes occur. Considerable attention has been given to the roles of uterine natural killer （uNK） cells in initiating decidual spiral arterial remodeling, a process normally completed by mid-gestation in mice and in humans. However, leukocyte roles in much earlier, region specific, decidual vascular remodeling are now being defined. Interest in immune cell-promoted vascular remodeling is driven by vascular aberrations that are reported in human gestational complications such as infertility, recurrent spontaneous abortion, preeclampsia （PE） and fetal growth restriction. Appropriate maternal cardiovascular responses during pregnancy protect mothers and their children from later cardiovascular disease risk elevation. One of the earliest uterine responses to pregnancy in species with hemochorial placentation is stromal cell decidualization, which creates unique niches for angiogenesis and leukocyte recruitment. In early decidua basalis, the aspect of the implantation site that will cradle the developing placenta and provide the major blood vessels to support mature placental functions, leukocytes are greatly enriched and display specialized properties. UNK cells, the most abundant leukocyte subset in early decidua basalis, have angiogenic abilities and are essential for normal early decidual angiogenesis. The regulation of uNK cells and their roles in determining maternal and progeny cardiovascular health over ore^nancv and PostPartum are discussed.