Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses

Elazzamy, Haidy; Dambaeva, Svetlana; Katukurundage, Dimantha; Garcia, M.D. Salazar; Skariah, Annie; Hussein, Youssef; Germain, A.; Fernández, E.; Gilman‐Sachs, Alice; Beaman, Kenneth D.; Kwak‐Kim, Joanne

doi:10.1111/aji.13024

Cited by 48 publications

(39 citation statements)

References 52 publications

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“…Most of the studies support the concept that in uRPL, the pregnancy-promoting functions of uNK are dysregulated in several ways. Indeed, in women with uRPL, higher concentrations of uNK have been detected than in normal fertile controls [92,[126][127][128][129][130][131], even though this finding has not always been consistent [132]. In other studies, despite no differences in the proportion of endometrial NK cells between controls and women with RPL, women with RPL have a significant decrease in the CD16 − CD56 bright NK cell subset, that is normally found in uncomplicated pregnancies [133]; this suggests that uNK cells in women with uRPL are quantitatively and qualitatively different from those normally found.…”

Section: Unksmentioning

confidence: 99%

“…The dysregulation of NK cells in the endometrium and decidua of women with RPL has potentially important consequences, leading to fatal pregnancy impairment. Particularly relevant in this context are the maintained cytotoxicity of uNK [23], the impaired capacity of uNK to properly interact with the specific HLA expressed by trophoblast [146][147][148], the impaired capacity of uNK to effectively participate in the full vascular remodeling of the uterine spiral arteries [129,149], the impaired capacity of uNK in limiting T cell cytotoxicity [61], and a disturbed cytokine production pattern by uNK [143,150,151].…”

Section: Unksmentioning

confidence: 99%

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Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Ticconi

Pietropolli

Simone

et al. 2019

IJMS

149

101

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Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal–fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

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Section: Unksmentioning

confidence: 99%

Section: Unksmentioning

confidence: 99%

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Ticconi

Pietropolli

Simone

et al. 2019

IJMS

149

101

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“…In contrast to HMB, we and others have shown increased endometrial vascular maturation in women with RPL (Quenby et al, 2009;El-Azzamy et al, 2018). We had also previously shown that immunoreactivity for TGFβ1 (vessels) was increased, and both TGFβRI (stromal cells, glandular epithelium, and vessels) and TGFβRII (vessels) decreased in the endometrium of women with RPL compared to controls (Lash et al, 2012).…”

Section: Discussionmentioning

confidence: 55%

“…Recurrent pregnancy loss is defined as two or more consecutive pregnancy losses; many cases are idiopathic (Quenby and Farquharson, 1993;Rai and Regan, 2006), although an altered endometrial environment may be a contributory factor to these idiopathic cases (Brosens and Gellersen, 2010). We and others have shown that women with a history of RPL have increased endometrial blood vessel maturity and blood flow (demonstrated by uterine artery Doppler) (Quenby et al, 2009;El-Azzamy et al, 2018). Embryo implantation occurs in a low oxygen environment (2-3% O 2 ) (Yedwab et al, 1976;Rodesch et al, 1992), with oxygen levels in the intervillous space rising to 6-8% O 2 between 10 and 12 weeks gestation (Jauniaux et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Transforming Growth Factor (TGF) β and Endometrial Vascular Maturation

Sun

Shivhare

et al. 2021

Front. Cell Dev. Biol.

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Appropriate growth and development of the endometrium across the menstrual cycle is key for a woman’s quality of life and reproductive well-being. Recurrent pregnancy loss (RPL) and heavy menstrual bleeding (HMB) affect a significant proportion of the female population worldwide. These endometrial pathologies have a significant impact on a woman’s quality of life as well as placing a high economic burden on a country’s health service. An underlying cause for both conditions is unknown in approximately 50% of cases. Previous research has demonstrated that aberrant endometrial vascular maturation is associated with both RPL and HMB, where it is increased in RPL but reduced in HMB. TGFβ1 is one of the key growth factors that regulate vascular maturation, by inducing phenotypic switching of vascular smooth muscle cells (VSMCs) from a synthetic phenotype to a more contractile one. Our previous data demonstrated an increase in TGFβ1 in the endometrium of RPL, while others have shown a decrease in women with HMB. However, TGFβ1 bioavailability is tightly controlled, and we therefore sought to perform an extensive immunohistochemical analysis of different components in the pathway in the endometrium of normal controls, women with HMB or RPL. In addition, two in vitro models were used to examine the role of TGFβ1 in endometrial vascular maturation and endothelial cell (EC):VSMC association. Taken all together, the immunohistochemical data suggest a decrease in bioavailability, receptor binding capacity, and signaling in the endometrium of women with HMB compared with controls. In contrast, there is an increase in the bioavailability of active TGFβ1 in the endometrium of women with RPL compared with controls. Endometrial explants cultured in TGFβ1 had an increase in the number of vessels associated with contractile VSMC markers, although the total number of vessels did not increase. In addition, TGFβ1 increased EC:VSMC association in an in vitro model. In conclusion, TGFβ1 is a key regulator of endometrial vascular maturation and could be considered as a therapeutic target for women suffering from HMB and/or RPL.

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“…In human, defective endovascular trophoblast invasion in the early first trimester could either lead to subsequent spontaneous abortion or the failure of spiral artery remodeling which leads to pre‐eclampsia . Recently, we reported the impaired spiral artery remodeling in women with RPL . Trophoblast invasion is mediated partially by matrix metalloproteinases (MMP), of which activity is regulated by pro‐inflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Mast cell–induced immunopathology in recurrent pregnancy losses

Derbala

Elazzamy

Bilal

et al. 2019

American J Rep Immunol

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Problem Mast cells (MC) have been known to play an important role in inflammation and angiogenesis by secreting numerous mediators, such as proteases, gelatinases, and proteoglycans. Three different MC subtypes were found in the endometrial layers of the uterus. In this study, we aim to investigate the role of endometrial MCs in recurrent pregnancy losses (RPL). Method of study Endometrial biopsy was performed 5‐7 days post‐ovulation (implantation window) in women with a history of two or more RPL (n = 46) and normal fertile women (n = 10). Quantitative RT‐PCR was performed to detect the expression of various mast cell mediators. Endometrial samples were evaluated using immunohistochemistry for c‐kit receptor (CD117) and tryptase (MC activation marker). Results Mast cells were present throughout the entire layers of the endometrium; their count was elevated in RPL patients as compared to controls. The gene expression of c‐Kit receptor was not different between the study groups. There are significant increases in the mRNA expression of various mediators, that is, stem cell factor (P = 0.029), tryptase (P = 0.024), heparan sulfate (P = 0.0005), and MMP‐2 (P < 0.0001) in women with RPL as compared to normal controls. Chymase gene expression was not detected in most of the endometrial samples. Conclusion This study has shown that MCs are overactive in RPL patients by creating a pro‐inflammatory milieu, suggesting a novel role in the immunopathology of RPL. Future studies are needed to better understand the role of MC in implantation and placental angiogenesis.

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Dysregulated uterine natural killer cells and vascular remodeling in women with recurrent pregnancy losses

Abstract: Increased uNK cells in mid-secretory endometrium are associated with increased vascularization and defective vascular transformation of spiral arteries in women with RPL.

Cited by 48 publications

References 52 publications

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

Transforming Growth Factor (TGF) β and Endometrial Vascular Maturation

Mast cell–induced immunopathology in recurrent pregnancy losses

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