Sean Leonard

A Review of Trafficking and Activation of Uterine Natural Killer Cells

Enrichment of uterine natural killer (uNK) cells occurs during pregnancy in many species. However, functions of uNK cells and regulation of their uterine homing are not fully defined. In mice and women, uNK cells contribute to angiogenesis, a role reviewed here and now addressed in a mammal with an alternative placental type.

Uterine NK cells in murine pregnancy

Murine uterine natural killer (uNK) cells are transient, short-lived, terminally differentiated lymphocytes found in decidualized endometrium. Cells expressing natural killer cell surface markers are present in uteri of infant mice. Terminal uNK cell differentiation coincides with mesometrial decidual development subsequent to blastocyst implantation and begins about gestation day 5. uNK cells proliferate rapidly and, within 3 days, senescent uNK cells appear in normal implantation sites. Mid-gestation, senescent cells become dominant and uNK cell numbers decline until term when remaining cells are shed with the placenta. Transplantable uNK cell progenitors occur outside the uterus, suggesting that blood cell homing augments any in-utero progenitors. Early in healthy pregnancies, uNK cells produce cytokines and angiogenic molecules. Their lytic capacity in normal gestation and in pregnancy failure is incompletely defined. A significant shift recently occurred in thinking about major uNK cell functions. Activated uNK cells are now considered critical for appropriate endometrial angiogenesis in early implantation site development and in non-gestational endometrium. Because analogous cells appear in the endometria of women during each menstrual cycle and become abundant in early pregnancy, studies involving experimental pregnancy termination in genetically manipulated mice continue to have great importance for understanding regulation at the human maternal-fetal interface.

Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy.

Citation Burke SD, Barrette VF, Gravel J, Carter ALI, Hatta K, Zhang J, Chen Z, Leno‐Durán E, Bianco J, Leonard S, Murrant C, Adams MA, Anne Croy B. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010

REVIEW ARTICLE: Uterine NK Cells, Spiral Artery Modification and the Regulation of Blood Pressure During Mouse Pregnancy

Citation Burke SD, Barrette VF, Gravel J, Carter ALI, Hatta K, Zhang J, Chen Z, Leno‐Durán E, Bianco J, Leonard S, Murrant C, Adams MA, Anne Croy B. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010

Gestational Modification of Murine Spiral Arteries Does Not Reduce Their Drug-Induced Vasoconstrictive Responses In Vivo

ABSTRACT Dynamic control of maternal blood flow to the placenta is critical for healthy pregnancy. In many tissues, microvasculature arteries control the flow. The uterine/endometrial vascular bed changes during pregnancy include physiological remodeling of spiral arteries from constricted artery-like structures to dilated vein-like structures between Gestation Day 8 (gd8) and gd12 in mice and wk 12–16 in humans. These changes occur, in part, due to local environmental changes such as decidualization, recruitment of maternal uterine natural killer cells, and invasion of conceptus-derived trophoblasts. No current preparations permit in vivo testing of decidual microvascular reactivity. We report an in vivo intravital fluorescence microscopy model that permits functional study of the entire uterine microvascular bed (uterine, arcuate, radial, basal, and spiral arteries) in gravid C57BL/6 mice. Vascular reactivities were measured at gd8 prespiral arterial remodeling and gd12 (postremodeling) to a range of concentrations of adenosine (10−8–10−6 M), acetylcholine (10−7–10−5 M), phenylephrine (10−7–10−5 M), and angiotensin II (10−8–10−6 M). At baseline, each arterial branch order was significantly more dilated on gd12 than gd8. Each microvascular level responded to each agonist on gd8 and gd12. At gd12, vasodilation to adenosine was attenuated in uterine, arcuate, and basal arteries, while constrictor activity to angiotensin II was enhanced in uterine and arcuate arteries. The tendency for increasing vasoconstriction between gd8 to gd12 and the constrictor responses of modified spiral arteries were unexpected findings that may reflect influences of the intact in vivo environment rather than inherent properties of the vessels and may be relevant to ongoing human pregnancies.

Arteriolar reactivity in lymphocyte-deficient mice

Mounting evidence suggests that lymphocytes have the capacity to contribute to the regulation of systemic circulatory control. We postulated that T and natural killer (NK) cells could modify basal microvascular activity under physiologically normal conditions. In situ intravital microscopy of mouse cremaster vasculature was used to evaluate arteriolar reactivities to the vasoconstrictors angiotensin II (ANG II) and phenylephrine (Phe) and the vasodilators acetylcholine (ACh) and adenosine (Ado) in normal [+/+; wild type (WT)] and genetically immunodeficient (T(-)B(-)NK(+) or T(-)B(-)\NK(-)) C57BL/6 and BALB/c mice, strain backgrounds with differentially polarized T cell cytokine production. Immunodeficient mice tended to have smaller baseline and maximal diameters of third-order cremaster arterioles than their congenic WT partners. In C57BL/6, baseline diameters were similar in T-B(-) mice without or with NK cells; in BALB/c, baseline diameters were larger in T-B-NK(-) mice than in T(-)B(-)NK(+) mice. Thus, at baseline, lymphocytes tended to promote vasodilation, except BALB/c NK cells, which mediated mild vasoconstriction. The presence of NK cells suppressed dilations to Ado in both strains, to ACh in the C57BL/6 strain, and dilatory responses to ANG II in C57BL/6 and to Phe in BALB/c. In the BALB/c strain, the presence of T and B cells promoted vasodilatory responses to Ado, attenuated dilations to low ACh concentrations, and exaggerated dilation and constriction responses to ANG II. Thus, under agonist challenge, NK cells generally promote constriction, whereas influences of T and B cells depend upon the stimulus. Therefore, lymphocytes or their products have physiological influences on microvascular arteriolar reactivity.

Uterine NK Cells, Spiral Artery Modification and the Regulation of Blood Pressure During Mouse Pregnancy: UNK CELLS IN PREGNANCY VASCULAR ADAPTATIONS

Citation Burke SD, Barrette VF, Gravel J, Carter ALI, Hatta K, Zhang J, Chen Z, Leno‐Durán E, Bianco J, Leonard S, Murrant C, Adams MA, Anne Croy B. Uterine NK cells, spiral artery modification and the regulation of blood pressure during mouse pregnancy. Am J Reprod Immunol 2010