Baboon placental heparin-binding epidermal growth factor-like growth factor

Placental extravillous trophoblast remodeling of the uterine spiral arteries is important for promoting blood flow to the placenta and fetal development. Heparin-binding EGF-like growth factor (HB-EGF), an EGF family member, stimulates differentiation and invasive capacity of extravillous trophoblasts in vitro. Trophoblast expression and maternal levels of HB-EGF are reduced at term in women with preeclampsia, but it is uncertain whether HB-EGF is downregulated earlier when it may contribute to placental insufficiency. A nonhuman primate model has been established in which trophoblast remodeling of the uterine spiral arteries is suppressed by shifting the rise in estrogen from the second to the first trimester of baboon pregnancy. In the present study, we used this model to determine if placental HB-EGF is altered by prematurely elevating estrogen early in baboon gestation. Uterine spiral artery remodeling and placental expression of HB-EGF and other EGF family members were assessed on day 60 of gestation in baboons treated with estradiol (E2) daily between days 25 and 59 of gestation (term = 184 days). The percentages of spiral artery remodeling were 90, 84 and 70% lower (P < 0.01), respectively, for vessels of 26–50, 51–100 and >100 µm diameter in E2-treated compared with untreated baboons. HB-EGF protein quantified by immunocytochemical staining/image analysis was decreased three-fold (P < 0.01) in the placenta of E2-treated versus untreated baboons, while amphiregulin (AREG) and EGF expression was unaltered. Therefore, we propose that HB-EGF modulates the estrogen-sensitive remodeling of the uterine spiral arteries by the extravillous trophoblast in early baboon pregnancy.

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Maternal Systemic Vascular Dysfunction in a Primate Model of Defective Uterine Spiral Artery Remodeling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00613.2020 ◽

2021 ◽

Author(s):

Eugene D. Albrecht ◽

Jeffery S. Babischkin ◽

Graham W. Aberdeen ◽

Marcia G. Burch ◽

Gerald J. Pepe

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Vascular Function ◽

First Trimester ◽

Vascular Endothelial ◽

Spiral Artery ◽

Primate Model ◽

Placental Perfusion ◽

Arterial Blood ◽

Artery Remodeling

Uterine spiral artery remodeling (UAR) is essential for placental perfusion and fetal development. A defect in UAR underpins placental ischemia disorders, e.g. preeclampsia, that result in maternal systemic vascular endothelial oxidative stress and dysfunction and hypertension. We have established a model of impaired UAR by prematurely elevating maternal serum estradiol levels during the first trimester of baboon pregnancy. However, it is unknown whether this experimental paradigm is associated with maternal vascular endothelial dysfunction. Therefore, in the present study baboons were administered estradiol on days 25-59 of gestation to suppress UAR and vascular function determined in maternal skeletal muscle obtained on day 165 (term = 184 days). Maternal peripheral serum sFlt-1 levels were 3-fold higher (P <0.05) and skeletal muscle arteriolar endothelial nitric oxide synthase protein expression and luminal area, and skeletal muscle capillary density, were 30-50% lower (P < 0.01) near term in UAR suppressed baboons. Maternal skeletal muscle catalase protein levels, reflecting oxidative stress, were 75% higher (P < 0.05) and mean arterial blood pressure 28% higher (P < 0.01) in UAR defective baboons. We propose that these changes in skeletal muscle, a systemic tissue, were induced by the elevation in sFlt-1, which suppresses vascular endothelial growth factor bioavailability. In summary, maternal skeletal muscle vascular function was disrupted in a baboon model of impaired UAR. These results highlight the translational impact of this primate model and relevance to adverse conditions of human pregnancy underpinned by improper uterine artery transformation.

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Overexpression of miR-210-3p Impairs Extravillous Trophoblast Functions Associated with Uterine Spiral Artery Remodeling

International Journal of Molecular Sciences ◽

10.3390/ijms22083961 ◽

2021 ◽

Vol 22 (8) ◽

pp. 3961

Author(s):

Heyam Hayder ◽

Guodong Fu ◽

Lubna Nadeem ◽

Jacob A. O’Brien ◽

Stephen J. Lye ◽

...

Keyword(s):

First Trimester ◽

Extravillous Trophoblast ◽

Migration And Invasion ◽

Mrna Levels ◽

Spiral Artery ◽

Placental Development ◽

Homeobox Transcription Factor ◽

Endovascular Trophoblast ◽

Artery Remodeling ◽

Trophoblast Migration

Hsa-miR-210-3p has been reported to be upregulated in preeclampsia (PE); however, the functions of miR-210-3p in placental development are not fully understood, and, consequently, miR-210-3p’s role in the pathogenesis of PE is still under investigation. In this study, we found that overexpression of miR-210-3p reduced trophoblast migration and invasion, extravillous trophoblast (EVT) outgrowth in first trimester explants, expression of endovascular trophoblast (enEVT) markers and the ability of trophoblast to form endothelial-like networks. In addition, miR-210-3p overexpression significantly downregulated the mRNA levels of interleukin-1B and -8, as well as CXC motif ligand 1. These cytokines have been suggested to play a role in EVT invasion and the recruitment of immune cells to the spiral artery remodeling sites. We also showed that caudal-related homeobox transcription factor 2 (CDX2) is targeted by miR-210-3p and that CDX2 downregulation mimicked the observed effects of miR-210-3p upregulation in trophoblasts. These findings suggest that miR-210-3p may play a role in regulating events associated with enEVT functions and its overexpression could impair spiral artery remodeling, thereby contributing to PE.

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B‐flow/spatiotemporal image correlation M‐mode: a novel ultrasound method that detects a decrease in spiral artery luminal diameter in the first trimester in a primate model of impaired spiral artery remodeling

Ultrasound in Obstetrics and Gynecology ◽

10.1002/uog.23753 ◽

2021 ◽

Author(s):

O. M. Turan ◽

J. S. Babischkin ◽

G. W. Aberdeen ◽

S. Turan ◽

C. R. Harman ◽

...

Keyword(s):

First Trimester ◽

Image Correlation ◽

Spiral Artery ◽

Primate Model ◽

Luminal Diameter ◽

Ultrasound Method ◽

Artery Remodeling ◽

Spatiotemporal Image Correlation ◽

Mode A

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Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation

Development ◽

10.1242/dev.120.5.1071 ◽

1994 ◽

Vol 120 (5) ◽

pp. 1071-1083 ◽

Cited By ~ 31

Author(s):

S.K. Das ◽

X.N. Wang ◽

B.C. Paria ◽

D. Damm ◽

J.A. Abraham ◽

...

Keyword(s):

Growth Factor ◽

Egf Receptor ◽

Heparan Sulphate ◽

Luminal Epithelium ◽

Heparin Binding ◽

Mouse Uterus ◽

Growth Factor Gene ◽

Heparan Sulphate Proteoglycans ◽

Egf Family

Heparin-binding EGF-like growth factor (HB-EGF) is a newly discovered member of the EGF family of growth factors. HB-EGF can bind to two loci on cell surfaces, heparan sulphate proteoglycans and EGF-receptor (EGF-R), and either one or both of these interactions could play a role in cell-cell interactions. In the rodent, increased endometrial vascular permeability at the site of blastocyst apposition is considered to be an earliest discernible prerequisite event in the process of implantation and this event coincides with the initial attachment reaction between the blastocyst trophectoderm and uterine luminal epithelium. This investigation demonstrates that the HB-EGF gene is expressed in the mouse uterine luminal epithelium surrounding the blastocyst 6–7 hours before the attachment reaction that occurs at 2200–2300 hours on day 4 of pregnancy. It was further demonstrated that this gene is not expressed in the luminal epithelium at the site of the blastocyst apposition during the progesterone-maintained delayed implantation, but is readily induced in the luminal epithelium surrounding an activated blastocyst after termination of the delay by an estrogen injection. In vitro studies showed that HB-EGF induced blastocyst EGF-R autophosphorylation, and promoted blastocyst growth, zona-hatching and trophoblast outgrowth. These results suggest possible interactions between the uterine HB-EGF and blastocyst EGF-R very early in the process of implantation, earlier than any other embryo-uterine interactions defined to date at the molecular level.

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Heme oxygenase-1 gene modified human placental mesenchymal stem cells promote placental angiogenesis and spiral artery remodeling by improving the balance of angiogenic factors in vitro

Placenta ◽

10.1016/j.placenta.2020.07.007 ◽

2020 ◽

Vol 99 ◽

pp. 70-77

Author(s):

Di Wu ◽

Yu Liu ◽

XiaoXia Liu ◽

WeiFang Liu ◽

HaoRan Shi ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Heme Oxygenase ◽

Angiogenic Factors ◽

Heme Oxygenase 1 ◽

Spiral Artery ◽

Placental Angiogenesis ◽

Placental Mesenchymal Stem Cells ◽

Artery Remodeling

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Uterine decidual niche modulates the progressive dedifferentiation of spiral artery vascular smooth muscle cells during human pregnancy†

Biology of Reproduction ◽

10.1093/biolre/ioaa208 ◽

2020 ◽

Author(s):

Yeling Ma ◽

Xin Yu ◽

Lanmei Zhang ◽

Juan Liu ◽

Xuan Shao ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Vascular Remodeling ◽

Dynamic Change ◽

Muscle Cells ◽

Extravillous Trophoblast ◽

Spiral Artery

Abstract Uterine spiral artery (SPA) remodeling is a crucial event during pregnancy to provide enough blood supply to maternal–fetal interface and meet the demands of the growing fetus. Along this process, the dynamic change and the fate of spiral artery vascular smooth muscle cells (SPA–VSMCs) have long been debatable. In the present study, we analyzed the cell features of SPA–VSMCs at different stages of vascular remodeling in human early pregnancy, and we demonstrated the progressively morphological change of SPA–VSMCs at un-remodeled (Un-Rem), remodeling, and fully remodeled (Fully-Rem) stages, indicating the extravillous trophoblast (EVT)-independent and EVT-dependent phases of SPA–VSMC dedifferentiation. In vitro experiments in VSMC cell line revealed the efficient roles of decidual stromal cells, decidual natural killer cells (dNK), decidual macrophages, and EVTs in inducing VSMCs dedifferentiation. Importantly, the potential transformation of VSMC toward CD56+ dNKs was displayed by immunofluorescence-DNA in-situ hybridization-proximity ligation and chromatin immunoprecipitation assays for H3K4dime modification in the myosin heavy chain 11 (MYH11) promoter region. The findings clearly illustrate a cascade regulation of the progressive dedifferentiation of SPA–VSMCs by multiple cell types in uterine decidual niche and provide new evidences to reveal the destination of SPA–VSMCs during vascular remodeling.

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The Gene for Heparin-Binding Epidermal Growth Factor-Like Growth Factor is Stress-Inducible: Its Role in Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199903000-00009 ◽

1999 ◽

Vol 19 (3) ◽

pp. 307-320 ◽

Cited By ~ 45

Author(s):

Nobutaka Kawahara ◽

Kazuhiko Mishima ◽

Shigeki Higashiyama ◽

Naoyuki Taniguchi ◽

Akira Tamura ◽

...

Keyword(s):

Cerebral Ischemia ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Dentate Gyrus ◽

Transforming Growth Factor ◽

Adult Brain ◽

Normal Brain ◽

Heparin Binding ◽

Epidermal Growth ◽

Egf Family

The functions of the epidermal growth factor (EGF) family members in the adult brain are not known. This study investigated the changes in the expression of members of the EGF family following global ischemia employing in situ hybridization and immunohistochemical techniques to elucidate their roles in pathological conditions. EGF mRNA was not detected in either the control or the postischemic rat brain. Although transforming growth factor-α (TGF-α) mRNA was widely expressed in the normal brain, its expression did not change appreciably following ischemia. By contrast, heparin-binding EGF-like growth factor (HB-EGF) mRNA expression was rapidly increased in the CA3 sector and the dentate gyrus of the hippocampus, cortex, thalamus, and cerebellar granule and Purkinje cell layers. EGF receptor mRNA, which was widely expressed, also showed an increase in the CA3 sector and dentate gyrus. Conversely, HB-EGF mRNA did not show any increase prior to ischemic neuronal injury in the CA1 sector, the region most vulnerable to ischemia. Immunohistochemical detection of HB-EGF in the postischemic brain suggested a slight increase of immunostaining in the dentate gyrus of the hippocampus and the cortex. These findings showed that the gene encoding HB-EGF is stress-inducible, indicating the like-lihood that HB-EGF is a neuroprotective factor in cerebral ischemia.

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