Growth arrest-specific protein-6/AXL signaling induces preeclampsia in rats†

Hirschi, Kelsey M.; Tsai, Kary Y F; Davis, Taylor; Clark, Jeliyah; Knowlton, Marjorie; Bikman, Benjamin T.; Reynolds, Paul; Arroyo, Juan A.

doi:10.1093/biolre/ioz140

Cited by 13 publications

(21 citation statements)

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“…However, the maternal Gas6 serum levels are significantly increased in PE during pregnancy ( Stepan et al, 2013 ). Gas6/Axl signaling is capable of inducing PE in pregnant rats ( Hirschi et al, 2020 ). Therefore, the expression of Gas6 in PE is controversial.…”

Section: Discussionmentioning

confidence: 99%

Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

et al. 2021

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Preeclampsia (PE), a severe pregnancy-specific syndrome, is characterized by impaired placental angiogenesis. Although the pathogenesis of this condition remains largely unclear, vascular systemic endothelial injury is thought to be the common contributing factor. Soluble Axl (sAxl), a biomarker of endothelial dysfunction, is known to be abnormally increased in a variety of diseases associated with vascular injury. In a previous study, we found that the plasma levels of sAxl were significantly higher in PE with severe features (sPE) than in pregnant women who did not have PE. The current study aimed to further explore the potential role of sAxl in vascular injury in patients with sPE. We found that the upregulation of sAxl in maternal plasma was positively correlated with the plasma levels of sFlt-1 and negatively correlated with placental NO synthase (eNOS) in women with sPE. Furthermore, elevated levels of sAxl suppressed proliferation and endothelial tube formation and promoted cytotoxicity in human umbilical vein endothelial cells (HUVECs) through the downregulation of p-Akt, p-p70S6K, p-mTOR, and Grb2. Subsequently, we established a pregnant rat model with PE-like characteristics by injecting pregnant rats with an adenovirus expressing sAxl. These rats exhibited a typical PE-like phenotype, including increased blood pressure, proteinuria, and fetal growth restriction, along with abnormal placental and fetal renal morphology. In conclusion, our study demonstrated the role of sAxl in systemic vascular injury through the regulation of the expression of key molecules of angiogenesis and described its potential contribution to the development of sPE.

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Section: Discussionmentioning

confidence: 99%

Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

et al. 2021

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“…CEBPB (CCAAT enhancer binding protein beta) [38], ACSL4 [39], MBD2 [40], ULK1 [41], NUCB2 [42], TWIST1 [43], HOOK2 [44], CLDN7 [45], TBK1 [46], YIPF6 [47], TFRC (transferrin receptor) [48], ENPP2 [49], SLIT2 [50], MFGE8 [51], FAT1 [52], GPC4 [53], COL6A3 [54], EGFL6 [55], AOC3 [56], CCN2 [57], LYVE1 [58], RARA (retinoic acid receptor alpha) [59], COL18A1 [60], THY1 [61], CD36 [62], PEMT (phosphatidylethanolamine N-methyltransferase) [63], AIF1L [64], OXTR (oxytocin receptor) [65], LMNA (lamin A/C) [66], CXCL14 [67], DKK3 [68], ANGPTL2 [69] and CMTM7 [70] were reported to be associated with obesity, but these genes might be linked with progression of GDM. AHR (aryl hydrocarbon receptor) [71], STS (steroid sulfatase) [72], PLAC1 [73], CYP11A1 [74], PSG11 [75], STAT5B [76], TLR3 [77], FOLR1 [78], HSPB1 [79], HSP90AA1 [80], ANXA4 [81], ATF3 [82], DAPK1 [83], ENTPD1 [84], ABL1 [85], VSIG4 [86], CD99 [87], VWF (von Willebrand factor) [88], PODXL (podocalyxin like) [89], PDPN (podoplanin) [90], RND3 [91], VCAN (versican) [92], AXL (AXL receptor tyrosine kinase) [93], PIEZO1 [94], GAS6 [93], LAMA4 [95], CAV1 [96], DLL1 [97], CD44 [98], CD81 [99], SMAD3 [100], NES (nestin) [101], DCN (decorin) [102], AGTR1 [103], SLIT3 [104], B2M [105], STAT3 [106], STC1 [107] and ADAMTS1 [108] were shown to participate in facilitating the preeclampsia. Majchrzak-Celiń ka et al [109] ...…”

Section: Discussionmentioning

confidence: 99%

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus

Vastrad¹,

Vastrad²,

Tengli

2021

Preprint

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Gestational diabetes mellitus (GDM) is one of the metabolic diseases during pregnancy. The identification of the central molecular mechanisms liable for the disease pathogenesis might lead to the advancement of new therapeutic options. The current investigation aimed to identify central differentially expressed genes (DEGs) in GDM. The transcription profiling by array data (E-MTAB-6418) was obtained from the ArrayExpress database. The DEGs between GDM samples and non GDM samples were analyzed with limma package. Gene ontology (GO) and REACTOME enrichment analysis were performed using ToppGene. Then we constructed the protein-protein interaction (PPI) network of DEGs by the Search Tool for the Retrieval of Interacting Genes database (STRING) and module analysis was performed. Subsequently, we constructed the miRNA-hub gene network and TF-hub gene regulatory network by the miRNet database and NetworkAnalyst database. The validation of hub genes was performed through receiver operating characteristic curve (ROC). Finally, the candidate small molecules as potential drugs to treat GDM were predicted by using molecular docking. Through transcription profiling by array data, a total of 869 DEGs were detected including 439 up regulated and 430 down regulated genes. Biological process analysis of GO enrichment analysis showed these DEGs were mainly enriched in reproduction, nuclear outer membrane-endoplasmic reticulum membrane network, identical protein binding, cell adhesion, supramolecular complex and signaling receptor binding. Signaling pathway enrichment analysis indicated that these DEGs played a vital in cell surface interactions at the vascular wall and extracellular matrix organization. Ten genes, HSP90AA1, EGFR, RPS13, RBX1, PAK1, FYN, ABL1, SMAD3, STAT3, and PRKCA in the center of the PPI network, modules, miRNA-hub gene regulatory network and TF-hub gene regulatory network were associated with GDM, according to ROC analysis. Finally, the most significant small molecules were predicted based on molecular docking. Our results indicated that HSP90AA1, EGFR, RPS13, RBX1, PAK1, FYN, ABL1, SMAD3, STAT3, and PRKCA could be the potential novel biomarkers for GDM diagnosis, prognosis and the promising therapeutic targets. The current might be essential to understanding the molecular mechanism of GDM initiation and development.

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“…Some other attempts to model maternal hypertension/preeclampsia in the rat and examine the consequences on intrauterine trophoblast cell guided uterine spiral artery remodeling include maternal hyperinsulinemia, inhibition of heme oxygenase (HO), and treatment with growth arrest-specific 6 (GAS6) [ 160 , 161 , 162 , 163 , 164 ]. All manipulations resulted in elevated blood pressure and intrauterine growth restriction but caused a range of phenotypes at the uterine-placental interface.…”

Section: Experimental Manipulation Of Trophoblast Cell Invasion and U...mentioning

confidence: 99%

Modeling Trophoblast Cell-Guided Uterine Spiral Artery Transformation in the Rat

Shukla

Soares

2022

IJMS

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The rat possesses hemochorial placentation with deep intrauterine trophoblast cell invasion and trophoblast-guided uterine spiral artery remodeling, which resembles human placentation. Uterine spiral arteries are extensively remodeled to deliver sufficient supply of maternal blood and nutrients to the developing fetus. Inadequacies in these key processes negatively impact fetal growth and development. Recent innovations in genome editing combined with effective phenotyping strategies have provided new insights into placental development. Application of these research approaches has highlighted both conserved and species-specific features of hemochorial placentation. The review provides foundational information on rat hemochorial placental development and function during physiological and pathological states, especially as related to the invasive trophoblast cell-guided transformation of uterine spiral arteries. Our goal is to showcase the utility of the rat as a model for in vivo mechanistic investigations targeting regulatory events within the uterine-placental interface.

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Growth arrest-specific protein-6/AXL signaling induces preeclampsia in rats†

Cited by 13 publications

References 85 publications

Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

Elevated Levels of Soluble Axl (sAxl) Regulates Key Angiogenic Molecules to Induce Placental Endothelial Dysfunction and a Preeclampsia-Like Phenotype

Integrated bioinformatics analysis reveals novel key biomarkers and potential candidate small molecule drugs in gestational diabetes mellitus

Modeling Trophoblast Cell-Guided Uterine Spiral Artery Transformation in the Rat

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