Intestinal microcirculation and necrotizing enterocolitis: The vascular endothelial growth factor system

Bowker, Rakhee M.; Yan, Xiaocai; Plaen, Isabelle G. De

doi:10.1016/j.siny.2018.08.008

Cited by 67 publications

(45 citation statements)

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“…NEC in both human infants and in animal models of the disease have revealed reduced intestinal proliferation in response to injury as well as impaired vascularization (Bowker, Yan, & De Plaen, 2018; Li et al, 2019; Pisano et al, 2020; Yan et al, 2016). Therefore, we assessed cell proliferation and vascularization within the intestine using immunohistochemical localization of antibodies against Ki67 and CD31, respectively.…”

Section: Resultsmentioning

confidence: 99%

Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Mokshagundam

Ding

Rumph

et al. 2020

Birth Defects Research

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Background: Necrotizing enterocolitis (NEC) is a rare, but potentially fatal intestinal inflammatory condition most often arising in premature infants. Infants provided formula are also at greater risk of developing this disease. Although the majority of formula-fed, preterm infants do not develop NEC, up to 30% of infants with the disease do not survive. Thus, identifying additional, currently unrecognized factors, which may predispose a specific infant to NEC development would be a significant clinical advancement. In this regard, we have previously reported that offspring of female or male mice with a history of developmental exposure to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit altered sensitivity to inflammatory challenges and are frequently born premature. Herein, we examined the possibility that, compared to unexposed mice (F1 NONE), developmental TCDD exposure of either parent (maternal, F1M TCDD , or paternal, F1P TCDD) would enhance the risk of NEC in offspring (F2 TCDD mice) in association with supplemental formula feeding. Methods: Beginning on postnatal day 7, all neonates were randomized to maternal milk only or maternal milk with up to 20 supplemental formula feedings. All pups remained with the Dams and were additionally allowed to nurse ad libitum. Results: Formula-fed F2 NONE pups rarely developed NEC while this disease was common in formula-fed F2M TCDD and F2P TCDD mice. Unexpectedly, 50% of F2M TCDD pups that were not provided supplemental formula also developed NEC. Conclusions: Our studies provide evidence that a history of parental TCDD exposure enhances the risk of NEC in offspring and suggest exposure to environmental immunotoxicants such as TCDD may also contribute to this inflammatory disease in humans.

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Section: Resultsmentioning

confidence: 99%

Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Mokshagundam

Ding

Rumph

et al. 2020

Birth Defects Research

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“…VEGF is an angiogenic protein that couples hypoxia sensing to angiogenesis and is necessary for the development and maintenance of capillary networks (9). It is suggested that VEGF-mediated alterations of the intestinal mucosal microvasculature play an important role in NEC pathogenesis (9,13,24,25). In fact, intestinal VEGF protein expression is reduced in human and experimental NEC (9,26).…”

Section: Discussionmentioning

confidence: 99%

“…It is suggested that VEGF-mediated alterations of the intestinal mucosal microvasculature play an important role in NEC pathogenesis (9,13,24,25). In fact, intestinal VEGF protein expression is reduced in human and experimental NEC (9,26). The VEGF gene is highly polymorphic, especially in the promoter, 5 ′untranslated and 3 ′ -untranslated regions (27).…”

Section: Discussionmentioning

confidence: 99%

“…Keywords: VEGF, IL-18, IL-4 receptor α-chain, polymorphisms, necrotizing enterocolitis, preterm INTRODUCTION Necrotizing enterocolitis (NEC) is the leading cause of morbidity and mortality from gastrointestinal disease in very and extremely preterm infants (1,2). As extensively discussed in several exhaustive reviews, the etiology of NEC is multifactorial and largely related to immaturity of the gastrointestinal tract (1)(2)(3)(4)(5)(6)(7)(8)(9). Besides low gestational age (GA), a complex interplay of other factors, such as type of feeding, gut dysbiosis, the high susceptibility of intestinal mucosal surface to inflammatory processes, or intestinal hypoperfusion may contribute to the pathogenesis of NEC (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

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confidence: 99%

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Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort

et al. 2020

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The etiology of necrotizing enterocolitis (NEC) is multifactorial and an underlying genetic predisposition to NEC is increasingly being recognized. A growing number of studies identified single nucleotide polymorphisms (SNPs) of selected genes with potential biological relevance in the development of NEC. However, few of these genetic studies have been replicated in validation cohorts. We aimed to confirm in a cohort of 358 preterm newborns (gestational age <30 weeks, 26 cases of NEC ≥ Bell stage II) the association with NEC of three candidate SNPs: the vascular endothelium growth factor (VEGF) C-2578A polymorphism (rs699947), the interleukin (IL)-18 C-607A polymorphism (rs1946518), and the IL-4 receptor α-chain (IL-4Rα) A-1902G polymorphism (rs1801275). We observed that allele and genotype frequencies of the three SNPs did not significantly differ between the infants with and without NEC. In contrast, the minor G-allele of the IL-4Rα A-1902G polymorphism was significantly less frequent in the group of 51 infants with the combined outcome NEC or death before 34 weeks postmenstrual age than in the infants without the outcome (0.206 vs. 0.331, P = 0.01). In addition, a significant negative association of the G-allele with the combined outcome NEC or death was found using the dominant (adjusted odds ratio, aOR: 0.44, 95% CI 0.21-0.92), recessive (aOR 0.15, 95% CI 0.03-0.74), and additive (aOR 0.46, 95% CI 0.26-0.80) genetic models. In conclusion our study provides further evidence that a genetic variant of the IL-4Rα gene may contribute to NEC.

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“…Mothers with preeclampsia, an important indication for antenatal MgSO 4 , were excluded because the maternal environment in this condition can affect vascular development of the intestine. [27,28]…”

Section: Discussionmentioning

confidence: 99%

Antenatal Magnesium Sulfate Reduced Intestinal Morbidities Requiring Surgery in Preterm Infants With Extremely Low Gestational Age: A Retrospective Cohort Study

Kim¹,

Kim²,

Shin³

et al. 2020

Preprint

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Background Antenatal magnesium sulfate is widely used as a tocolytic, for maternal seizures, and for seizure prophylaxis in preeclampsia. Recent studies have suggested that antenatal magnesium sulfate use is associated with favorable neurodevelopmental outcomes in preterm infants. However, there are concerns regarding the neonatal effects of antenatal magnesium sulfate, especially regarding gastrointestinal morbidities. This study aims to explore the effects of antenatal magnesium sulfate on intestinal morbidities requiring surgery in preterm infants.Methods This was a retrospective cohort study of 181 preterm infants who were born at less than 28 weeks of gestational age. Subjects were categorized as infants exposed to antenatal magnesium sulfate and those not exposed to antenatal magnesium sulfate.Results Antenatal magnesium sulfate was associated with a lower incidence of surgical conditions of the intestine (OR 0.393, 95% CI 0.170–0.905). Multivariate analysis showed that the duration of antenatal magnesium sulfate use was associated with surgical conditions of the intestine (adjusted OR 0.766, 95% CI 0.589–0.997). In the < 26 weeks of gestational age subgroup, use of antenatal magnesium sulfate was significantly associated with decreased intestinal morbidities requiring surgery (adjusted OR 0.234, 95% CI 0.060–0.922).Conclusion Antenatal magnesium sulfate use appears to have a protective effect on intestinal morbidities requiring surgery in preterm infants in a duration-dependent manner. Association of antenatal magnesium sulfate use and decreased intestinal morbidities requiring surgery was more distinct in preterm infants < 26 weeks of gestational age.

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Intestinal microcirculation and necrotizing enterocolitis: The vascular endothelial growth factor system

Cited by 67 publications

References 46 publications

Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Developmental 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Risk of Necrotizing Enterocolitis Associated With the Single Nucleotide Polymorphisms VEGF C-2578A, IL-18 C-607A, and IL-4 Receptor α-Chain A-1902G: A Validation Study in a Prospective Multicenter Cohort

Antenatal Magnesium Sulfate Reduced Intestinal Morbidities Requiring Surgery in Preterm Infants With Extremely Low Gestational Age: A Retrospective Cohort Study

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