Expression of the Vasoactive Proteins AT1, AT2, and ANP by Pregnancy-Induced Mouse Uterine Natural Killer Cells

Hatta, Kota; Carter, Alexandra L.; Chen, Zhilin; Leno-Durán, Ester; Ruiz‐Ruiz, Carmen; Olivares, Enrique G.; Tse, M. Yat; Pang, Stephen C.; Croy, B. Anne

doi:10.1177/1933719110385136

Cited by 23 publications

(16 citation statements)

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“…The hemodynamic and angiogenic influences lymphocytes and their products are emerging areas and further investigations are needed to understand how central their roles are for initiation and progression of preeclamptic pathology. 8,[34][35][36][37] Impaired SA remodeling is a key feature found amongst the "great obstetrical syndromes" . 38 In mice, we clearly show that, over the normal term of pregnancy, a maternal-fetal partnership exists that can resolve the hemodynamic changes imposed by this arterial pathology.…”

Section: Commentmentioning

confidence: 99%

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Zhang

Adams

Croy

2011

American Journal of Obstetrics and Gynecology

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OBJECTIVE-Our goal was to define mechanisms that protect murine pregnancies deficient in spiral arterial (SA) remodeling from hypertension, hypoxia and intra-uterine growth restriction.STUDY DESIGN-Micro-ultrasound analyses were conducted on virgin, gestation day (gd) 2,4,7,9,10,12,14,16,18 and postpartum BALB/c (WT) mice and BALB/c-Rag2 −/− /Il2rg −/− mice, an immunodeficient strain lacking SA remodeling. RESULTS-Rag2−/− /Il2rg −/− dams had normal SA flow velocities, greatly elevated uterine artery flow velocities between gd10-16 and smaller areas of placental flow from gd14 to term than controls. Maternal heart weight and output increased transiently. Conceptus alterations included higher flow velocities in the umbilical-placental circulation that became normal before term and bradycardia persistent to term.CONCLUSION-Transient changes in maternal heart weight and function accompanied by fetal circulatory changes successfully compensate for deficient SA modification in mice. Similar compensations in humans may contribute to post-partum pregnancy gains elevated risk of cardiovascular disease associated with preeclampsia.

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Section: Commentmentioning

confidence: 99%

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Zhang

Adams

Croy

2011

American Journal of Obstetrics and Gynecology

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“…5,6 Uterine natural killer (uNK) cells are the major immune cell population at the early fetomaternal interface where they regulate maternal uterine vasculature remodeling. 7 Differing from peripheral NK cells, uNK cells have unique tissue-related phenotypes and functions. They are mainly localized close to vessels in the decidua basalis (DB) and the mesometrial lymphoid aggregate of pregnancy (MLAp).…”

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confidence: 99%

Carbon Monoxide Promotes Proliferation of Uterine Natural Killer Cells and Remodeling of Spiral Arteries in Pregnant Hypertensive Heme Oxygenase-1 Mutant Mice

et al. 2014

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Abstract-Heme Oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO) promote implantation and placentation.Pregnancy disorders such as preeclampsia and intrauterine growth restriction are linked to both HO-1 diminution and impaired remodeling of maternal spiral arteries (SAs). Here, we investigated whether CO is able to prevent preeclampsia and intrauterine growth restriction through the modulation of uterine natural killer (uNK) cells that are necessary for initiation of SA remodeling. Hmox1 +/− or Hmox1 −/− implantations presented fewer uNK cell numbers and lower expression of uNK-related angiogeneic factors compared with Hmox1 +/+ sites. Quantitative histology revealed that Hmox1 +/− and Hmox1 −/− implantations had shallow SA development that was accompanied by intrauterine growth restriction and gestational hypertension. Application of CO at low dose during early to midgestation prevented intrauterine growth restriction in Hmox1 +/− mothers, this being associated with enhanced in situ proliferation of uNK cells and normalization of angiogenic parameters. Most importantly, CO improved SA remodeling and normalized blood pressure, ensuring a proper fetal growth. Thus, CO emerges as a key molecular player in pregnancy success by modulating uNK cells, which results in promotion of SA remodeling, adequate fetal support/growth, and prevention of hypertension. Linzke et al Targeting uNK Cells to Suppress Hypertension 581 Materials and Methods AnimalsFor analysis of implantation sites, Hmox1-competent or Hmox1-deficient BALB/c mice were used. These mice were initially provided by Dr Saw Feng-Yet and bred and maintained in our facility. The progeny obtained from breeding Hmox1 +/− female animals and Hmox1 +/− male animals were genotyped and recorded. C57BL/6 male animals were obtained from Charles River (Sulzfeld, Germany). The mice were maintained in our husbandry with a 12-hour light/ dark cycle and with food and water ad libitum. All experiments were approved by German authorities (Saxony-Anhalt's Ministry 2 -868).Hmox1 For all experiments, the detection of a vaginal plug indicated day 0 of pregnancy. Animals were euthanized on days 8, 10, 12, or 18 of pregnancy. Whole implantation sites for paraffin embedding were kept in 4% paraformaldehyde with 0.1% saccharose for 6 hours. For RNA isolation, tissue of MLAp and DB was carefully washed with cold sterile PBS (pH 7.4), snap frozen, and stored at −80°C. Tissue of MLAp and DB was stored in RPMI 1640 with 10% FBS and 1% penicillin and streptomycin for flow cytometry. CO InhalationFollowing our standard protocol, Hmox1 +/+ or Hmox1 +/− female animals were exposed to CO (50 ppm) day-long from day 3 to 8 of pregnancy. 5,6 Control animals inhaled the same air mixture without CO. The exposure of animals to mixed air or CO took place in cages placed in a 98-L Plexiglas animal chamber (A-Chamber; BioSpherix, NY). Duration of exposure and dosage was previously tested and established. Both time exposure and dose prevented fetal death without any toxic side effects. 5,6 Blo...

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“…In contrast to these findings that mimic inflammatory responses, our data support the idea that lymphocyte-derived molecules have physiological actions on stable microvessels under non-antigen-stimulated conditions, similar to how uNK cell-derived IFN␥ has a physiological role in promoting gestational structural change in implantation site arterioles (3). NK cells and T cells have been shown to have an intact renin-angiotensin system (29), T and B cells have an intact cholinergic system (30), and, recently, NK cells have been shown to produce atrial naturitic factor (22). Further work is needed to determine whether these and other vasoactive products are released from lymphocytes under homeostatic conditions.…”

Section: Discussionmentioning

confidence: 96%

“…There is growing evidence that T cells and NK cell lineages may participate in human and murine vascular regulation under nonpathological conditions. Human T and NK cells possess functional reninangiotensin systems (29), T and B cells contain all of the elements of the cholinergic signaling pathways, including nitric oxide synthesis (30), and, most recently, NK cells have been shown to produce atrial naturitic factor (22), indicating the potential for release of the vasoactive molecules besides classic cytokines. Interestingly, in normal healthy mouse and human pregnancy, the uterine vascular bed is strongly influenced by lymphocytes, specifically uterine (u) NK cells.…”

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Arteriolar reactivity in lymphocyte-deficient mice

Leonard

Croy

Murrant

2011

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Expression of the Vasoactive Proteins AT1, AT2, and ANP by Pregnancy-Induced Mouse Uterine Natural Killer Cells

Cited by 23 publications

References 45 publications

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Alterations in maternal and fetal heart functions accompany failed spiral arterial remodeling in pregnant mice

Carbon Monoxide Promotes Proliferation of Uterine Natural Killer Cells and Remodeling of Spiral Arteries in Pregnant Hypertensive Heme Oxygenase-1 Mutant Mice

Arteriolar reactivity in lymphocyte-deficient mice

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