Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis of placental microvascular endothelial cells during severe pre-eclampsia pathogenesis

Zhao, Lina; Ma, Ruixia; Zhang, Li; Yuan, Xiaolan; Wu, Jing; He, Lirong; Liu, Guocheng; Du, Rui

doi:10.1016/j.placenta.2019.06.375

Cited by 42 publications

(28 citation statements)

References 30 publications

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“…We have previously shown that lower extremity CVD during pregnancy is associated with some placental changes, such as extracellular matrix remodelling or increased placental apoptosis and villous calcification, along with increased expression of tissue hypoxia markers [10][11][12]. These mechanisms are also dysregulated at the placental level in other important vascular diseases, such as preeclampsia and intrauterine foetal growth restriction [13][14][15]. It should be highlighted how all these pathological conditions affect the process of angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

Ortega

Sáez

Fraile-Martínez

et al. 2020

IJMS

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Pregnancy is a period in a woman’s life associated with an increased risk of developing lower extremity chronic venous disease (CVD). Pregnancy-associated CVD is associated with changes in placental villi. We investigated angiogenesis and lymphangiogenesis in the placental villi of women with CVD during pregnancy compared with healthy controls with no history of CVD (HC). An observational, analytical, and prospective cohort study was conducted on 114 women in their third trimester of pregnancy (32 weeks). Sixty-two participants were clinically diagnosed with CVD. In parallel, 52 controls with no history of CVD (HC) were studied. Gene and protein expression of CD31, podoplanin (D2-40), Flt-1, and placental growth factor (PIGF) was analysed by real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry. CD31 and D2-40 gene expression was significantly greater in the placental villi of women with CVD, as were the numbers of vessels positive for CD31 and D2-40. Significantly higher gene and protein expression of Flt-1 and PIGF was observed in the placental villi of women with CVD. Histological analysis showed more placental villi with periodic acid of Schiff (PAS)-positive material in women with CVD. Our results show a connection between pregnancy-associated CVD and leading to higher proangiogenic and lymphangiogenic activity in placental villi.

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Section: Introductionmentioning

confidence: 99%

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

Ortega

Sáez

Fraile-Martínez

et al. 2020

IJMS

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“…and M. hominis), Chlamydia trachomatis and/or the growth of any bacteria except coagulase-negative Staphylococcus epidermidis [12,32]. For TLR2, TLR4, TLR6 and TLR9 receptors, their participation in angiogenesis, one of the key processes involved in the development and function of the placenta, has also been confirmed [14,[33][34][35]. TLR2 has been demonstrated to induce the expression of the angiogenic factor angiopoietin 2 (ANGPT2), as well as the MMP2 and MMP9 proteins, involved in destabilization and development of blood vessels [36].…”

Section: Introductionmentioning

confidence: 83%

Single Nucleotide Polymorphisms from CSF2, FLT1, TFPI and TLR9 Genes Are Associated with Prelabor Rupture of Membranes

Wujcicka

Kacerovský

Krekora

et al. 2021

Genes

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A prelabor rupture of membranes (PROM) and its subtypes, preterm PROM (pPROM) and term PROM (tPROM), are associated with disturbances in the hemostatic system and angiogenesis. This study was designed to demonstrate the role of single nucleotide polymorphisms (SNPs), localized in CSF2 (rs25881), FLT1 (rs722503), TFPI (C-399T) and TLR9 (rs352140) genes, in PROM. A population of 360 women with singleton pregnancy consisted of 180 PROM cases and 180 healthy controls. A single-SNP analysis showed a similar distribution of genotypes in the studied polymorphisms between the PROM or the pPROM women and the healthy controls. Double-SNP TT variants for CSF2 and FLT1 polymorphisms, CC variants for TLR9 and TFPI SNPs, TTC for CSF2, FLT1 and TLR9 polymorphisms, TTT for FLT1, TLR9 and TFPI SNPs and CCCC and TTTC complex variants for all tested SNPs correlated with an increased risk of PROM after adjusting for APTT, PLT parameters and/or pregnancy disorders. The TCT variants for the CSF2, FLT1 and TLR9 SNPs and the CCTC for the CSF2, FLT1, TLR9 and TFPI polymorphisms correlated with a reduced risk of PROM when corrected by PLT and APTT, respectively. We concluded that the polymorphisms of genes, involved in hemostasis and angiogenesis, contributed to PROM.

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“…The activation of TLR4 signaling pathway in the placenta promotes pro-inflammatory cytokines production through the upregulation of several transcription factors, including NF-κB , which can induce inflammatory responses and placental cytotrophoblast apoptosis 82 . Inhibition of HIF-1αmediated TLR4 activation can attenuate apoptosis and promote placental angiogenesis during severe preeclampsia 83 . Our results suggest that citrulline supplementation improves placental phenotype in DSSR, at least partly, by downregulating HIF-1α-mediated TLR4 activation in the placentas.…”

Section: Placental Inflammation and Fibrosismentioning

confidence: 99%

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

Man

Zhou

Lam

et al. 2021

Preprint

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Preeclampsia, characterized by hypertension, proteinuria, and fetal growth restriction, is one of the leading causes of maternal and perinatal mortality. By far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of L-citrulline supplementation in Dahl salt-sensitive rat, a model of superimposed preeclampsia. Parental DSSR were treated with L-citrulline (2.5 g/L in drinking water) from the day of mating to the end of lactation period. Blood pressure of the rats was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant DSSR was assessed by wire myograph. L-citrulline supplementation significantly reduced gestational hypertension, proteinuria, and levels of circulating soluble fms-like tyrosine kinase 1 in DSSR. L-citrulline improved maternal endothelial function by augmenting the production of nitric oxide in the aorta and improving endothelium-derived hyperpolarizing factor-mediated vasorelaxation in resistance arteries. L-citrulline supplementation improved placental insufficiency and fetal growth, which were associated with an enhancement of angiogenesis and reduction of fibrosis and senescence in the placentas. In addition, L-citrulline downregulated genes involved in the toll-like receptor 4 and nuclear factor-κB signaling pathway. In conclusion, this study shows that L-citrulline supplementation reduces gestational hypertension, improves placentation and fetal growth in a rat model of superimposed preeclampsia. L-citrulline supplementation may represent an effective and safe therapeutic strategy for preeclampsia that benefit both the mother and the fetus.

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Inhibition of HIF-1a-mediated TLR4 activation decreases apoptosis and promotes angiogenesis of placental microvascular endothelial cells during severe pre-eclampsia pathogenesis

Cited by 42 publications

References 30 publications

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

Increased Angiogenesis and Lymphangiogenesis in the Placental Villi of Women with Chronic Venous Disease during Pregnancy

Single Nucleotide Polymorphisms from CSF2, FLT1, TFPI and TLR9 Genes Are Associated with Prelabor Rupture of Membranes

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

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