Decreased PGF may contribute to trophoblast dysfunction in fetal growth restriction

Wu, Wei; Xu, Yin; Cheng, Weiwei; Yuan, Bo; Zhao, Jianan; Wang, Yanlin; Zhang, Huijuan

doi:10.1530/rep-17-0253

Cited by 17 publications

(11 citation statements)

References 48 publications

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“…Ang II is known to stimulate PGF expression via AT 1 R activation in human vascular endothelial cells (Pan et al 2010). FGR has also been shown by others to be associated with reduced placental PGF (Wu et al 2017).…”

Section: Discussionmentioning

confidence: 64%

Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

et al. 2019

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Fetal growth restriction (FGR) is a pregnancy complication wherein the foetus fails to reach its growth potential. The renin–angiotensin system (RAS) is a critical regulator of placental function, controlling trophoblast proliferation, angiogenesis and blood flow. The RAS significantly influences uteroplacental blood flow through the balance of its vasoconstrictive and vasodilatory pathways. Although the RAS is known to be dysregulated in placentae from women with preeclampsia, the expression of the RAS has not yet been studied in pregnancies compromised by FGR alone. This study investigated the mRNA expression and protein levels of RAS components in placentae from pregnancies compromised by FGR. Angiotensin II type 1 receptor (AGTR1) and angiotensin-converting enzyme 2 (ACE2) mRNA levels were reduced in FGR placentae compared with control (P = 0.012 and 0.018 respectively). Neprilysin (NEP) mRNA expression was lower in FGR placentae compared with control (P = 0.004). mRNA levels of angiotensinogen (AGT) tended to be higher in FGR placentae compared with control (P = 0.090). Expression of prorenin, AGT, angiotensin-converting enzyme (ACE) or ACE2 proteins were similar in control and FGR placentae. The renin-AGT reaction is a first order reaction so levels of expression of placental AGT determine levels of Ang II. Decreasing levels of ACE2 and/or NEP by limiting the production of Ang-(1-7), which is a vasodilator, and increasing placental Ang II levels (vasoconstrictor) may result in an imbalance between the vasoconstrictor and vasodilator arms of the placental RAS. Ultimately this dysregulation of the placental RAS could lead to reduced placental perfusion that is evident in FGR.

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Section: Discussionmentioning

confidence: 64%

Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

et al. 2019

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“…Therefore, we investigated whether inhibition of the phylogenetically related VEGFR could induce analgesia in rats. We treated rats with selective inhibitors targeting VEGFR-1 (Antczak et al, 2012;Wu et al, 2017), VEGFR-2 (Yakes et al, 2011), or VEGFR-3 (Alam et al, 2012. Cabozantinib, a VEGFR-2 inhibitor, caused mechanical analgesia.…”

Section: Vertebrate Pdgfr and Vegfr Signaling Modulates Mechanical Nomentioning

confidence: 99%

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

et al. 2019

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Mechanical sensitization is one of the most difficult clinical pain problems to treat. However, the molecular and genetic bases of mechanical nociception are unclear. Here we develop a Drosophila model of mechanical nociception to investigate the ion channels and signaling pathways that regulate mechanical nociception. We fabricated von Frey filaments that span the subthreshold to high noxious range for Drosophila larvae. Using these, we discovered that pressure (force/area), rather than force per se, is the main determinant of aversive rolling responses to noxious mechanical stimuli. We demonstrated that the RTK PDGF/VEGF receptor (Pvr) and its ligands (Pvfs 2 and 3) are required for mechanical nociception and normal dendritic branching. Pvr is expressed and functions in class IV sensory neurons, whereas Pvf2 and Pvf3 are produced by multiple tissues. Constitutive overexpression of Pvr and its ligands or inducible overexpression of Pvr led to mechanical hypersensitivity that could be partially separated from morphological effects. Genetic analyses revealed that the Piezo and Pain ion channels are required for mechanical hypersensitivity observed upon ectopic activation of Pvr signaling. PDGF, but not VEGF, peptides caused mechanical hypersensitivity in rats. Pharmacological inhibition of VEGF receptor Type 2 (VEGFR-2) signaling attenuated mechanical nociception in rats, suggesting a conserved role for PDGF and VEGFR-2 signaling in regulating mechanical nociception. VEGFR-2 inhibition also attenuated morphine analgesic tolerance in rats. Our results reveal that a conserved RTK signaling pathway regulates baseline mechanical nociception in flies and rats. Significance StatementHypersensitivity to touch is poorly understood and extremely difficult to treat. Using a refined Drosophila model of mechanical nociception, we discovered a conserved VEGF-related receptor tyrosine kinase signaling pathway that regulates mechanical nociception in flies. Importantly, pharmacological inhibition of VEGF receptor Type 2 signaling in rats causes analgesia and blocks opioid tolerance. We have thus established a robust, genetically tractable system for the rapid identification and functional analysis of conserved genes underlying mechanical pain sensitivity.

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“…PGF could induce trophoblastic cell invasion, which involves p70 phosphorylation. 33 Attenuation of PGF/Fms related tyrosine kinase 1 (FLT1) signaling is effective to suppress trophoblastic cell proliferative, invasive, and migratory potentials, 34 suggesting the involvement of PGF/FLT1 in the functions of trophoblast. Consistently, here we observed that PGF expression was downregulated in the PE group and was positively correlated with ZEB2-AS1 expression.…”

Section: Discussionmentioning

confidence: 99%

The decreased lncRNA ZEB2‐AS1 in pre‐eclampsia controls the trophoblastic cell line HTR‐8/SVneo's invasive and migratory abilities via the miR‐149/PGF axis

Gao

Sha

et al. 2019

J of Cellular Biochemistry

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Pre‐eclampsia (PE) is a pregnancy disease that causes maternal death and threatens the health of newborns. Accumulating evidence has revealed the essential roles of long noncoding RNAs (lncRNAs) in the progression of PE. The present investigation determined lncRNA ZEB2 antisense RNA 1 (ZEB2‐AS1) expression in PE and looked into the potential role of ZEB2‐AS1 in modulating trophoblastic cell functions. Quantitative real‐time polymerase chain reaction evaluated gene expression. Western blot analyzed the placental growth factor (PGF) protein level. Cell counting kit‐8 and Transwell invasion assays assessed the proliferative and invasive abilities of placental trophoblast cells, respectively. Wound healing assay determined cell migratory potentials. Dual‐luciferase reporter assay assessed the targeting relationship among ZEB2‐AS1, miR‐149, and PGF. Downregulation of lncRNA ZEB2‐AS1 was detected in placentas from patients with PE when compared with those from normal pregnancies. Moreover, ZEB2‐AS1 upregulation markedly promoted proliferative, migratory, and invasive potentials in HTR‐8/SVneo cells, while knockdown of ZEB2‐AS1 had the opposite effects. The effects on HTR‐8/SVneo cells mediated by ZEB2‐AS1 was correlated with the miR‐149/PGF axis. These findings indicate that ZEB2‐AS1 contributes to PE progression by affecting cell proliferative and invasive capacities via the miR‐149/PGF axis in HTR‐8/SVneo cells. In sum, we identified that ZEB2‐AS1 was a novel aberrantly expressed lncRNA in the placentas of PE patients and lncRNA ZEB2‐AS1 modulated trophoblastic cell line HTR‐8/SVneo's proliferative and invasive potentials via targeting the miR‐149/PGF axis.

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Decreased PGF may contribute to trophoblast dysfunction in fetal growth restriction

Cited by 17 publications

References 48 publications

Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

Dysregulation of the placental renin–angiotensin system in human fetal growth restriction

Growth Factor Signaling Regulates Mechanical Nociception in Flies and Vertebrates

The decreased lncRNA ZEB2‐AS1 in pre‐eclampsia controls the trophoblastic cell line HTR‐8/SVneo's invasive and migratory abilities via the miR‐149/PGF axis

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