Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodelling

Nakayama, Tomohiro; Kurobe, Hirotsugu; Sugasawa, Noriko; Kinoshita, Hajime; Higashida, Mayuko; Matsuoka, Yuki; Yoshida, Yasushi; Hirata, Yoichiro; Sakata, Masayo; Maxfield, Mark W.; Shimabukuro, Michio; Takahama, Yousuke; Sata, Masataka; Takahashi, Toshiaki; Kitagawa, Tetsuya; Tomita, Shuhei

doi:10.1093/cvr/cvt146

Cited by 43 publications

(36 citation statements)

References 36 publications

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“…A,B), strongly suggesting that gut resident macrophages may be exposed to local changes in oxygen levels that could impact macrophage function. Previous studies suggest that exposure of macrophages to hypoxic conditions can induce expression of the transcription factor hypoxia‐inducible factor (HIF), a key regulator of cellular responses to hypoxic conditions . HIF1α in particular has recently been shown to be responsible for IFNγ expression in macrophages following exposure to hypoxic conditions .…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies suggest that exposure of macrophages to hypoxic conditions can induce expression of the transcription factor hypoxia-inducible factor (HIF), a key regulator of cellular responses to hypoxic conditions. [50][51][52][53][54] HIF1α in particular has recently been shown to be responsible for IFNγ expression in macrophages following exposure to hypoxic conditions. 55 As a result, we next defined the impact of neonatal anemia on HIF1α expression in intestinal macrophages.…”

Section: Resultsmentioning

confidence: 99%

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Anemia induces gut inflammation and injury in an animal model of preterm infants

et al. 2019

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BACKGROUND While very low birth weight (VLBW) infants often require multiple red blood cell transfusions, efforts to minimize transfusion‐associated risks have resulted in more restrictive neonatal transfusion practices. However, whether restrictive transfusion strategies limit transfusions without increasing morbidity and mortality in this population remains unclear. Recent epidemiologic studies suggest that severe anemia may be an important risk factor for the development of necrotizing enterocolitis (NEC). However, the mechanism whereby anemia may lead to NEC remains unknown. STUDY DESIGN AND METHODS The potential impact of anemia on neonatal inflammation and intestinal barrier disruption, two well‐characterized predisposing features of NEC, was defined by correlation of hemoglobin values to cytokine levels in premature infants and by direct evaluation of intestinal hypoxia, inflammation and gut barrier disruption using a pre‐clinical neonatal murine model of phlebotomy‐induced anemia (PIA). RESULTS Increasing severity of anemia in the preterm infant correlated with the level of IFN‐gamma, a key pro‐inflammatory cytokine that may predispose an infant to NEC. Gradual induction of PIA in a pre‐clinical model resulted in significant hypoxia throughout the intestinal mucosa, including areas where intestinal macrophages reside. PIA‐induced hypoxia significantly increased macrophage pro‐inflammatory cytokine levels, while reducing tight junction protein ZO‐1 expression and increasing intestinal barrier permeability. Macrophage depletion reversed the impact of anemia on intestinal ZO‐1 expression and barrier function. CONCLUSIONS Taken together, these results suggest that anemia can increase intestinal inflammation and barrier disruption likely through altered macrophage function, leading to the type of predisposing intestinal injury that may increase the risk for NEC.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Anemia induces gut inflammation and injury in an animal model of preterm infants

et al. 2019

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“…Unfortunately, in vivo studies do not always provide consistent findings. In a wire-induced vascular injury model, myeloid HIF-1α promotes vascular inflammation and remodeling manifested by increases in TNF-α and IL-6 levels proximal to the injury site and neointimal thickening of injured arteries (125). However, a recent in vivo genetic and drug-based approach suggested the opposite effect in a different mouse model, indicating that HIF-1α and HIF-2α accumulation correlates with reduced atherosclerosis development.…”

Section: Hifs In Myeloid Cellsmentioning

confidence: 99%

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Lin¹,

Simon²

2016

Journal of Clinical Investigation

119

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“…Moreover, myeloid-specific deletion of Hif-1α causes abnormalities in the motility, adhesion and invasiveness of peritoneal macrophages22. Interestingly, a recent study has suggested that HIF-1α plays a critical role in macrophages during vascular remodelling after femoral artery injury23. However, how HIF-1α regulates macrophage function during vascular development and blood vessel repair remains poorly understood.…”

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confidence: 99%

Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish

et al. 2017

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Macrophages are known to interact with endothelial cells during developmental and pathological angiogenesis but the molecular mechanisms modulating these interactions remain unclear. Here, we show a role for the Hif-1α transcription factor in this cellular communication. We generated hif-1aa;hif-1ab double mutants in zebrafish, hereafter referred to as hif-1α mutants, and find that they exhibit impaired macrophage mobilization from the aorta-gonad-mesonephros (AGM) region as well as angiogenic defects and defective vascular repair. Importantly, macrophage ablation is sufficient to recapitulate the vascular phenotypes observed in hif-1α mutants, revealing for the first time a macrophage-dependent angiogenic process during development. Further substantiating our observations of vascular repair, we find that most macrophages closely associated with ruptured blood vessels are Tnfα-positive, a key feature of classically activated macrophages. Altogether, our data provide genetic evidence that Hif-1α regulates interactions between macrophages and endothelial cells starting with the mobilization of macrophages from the AGM.

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Role of macrophage-derived hypoxia-inducible factor (HIF)-1α as a mediator of vascular remodelling

Abstract: Our results show that HIF-1α in macrophages plays a crucial role in promoting vascular inflammation and remodelling. As decreasing HIF-1α activity in macrophages may prevent the progression of vascular remodelling, HIF-1α may be a possible therapeutic target in vascular diseases.

Cited by 43 publications

References 36 publications

Anemia induces gut inflammation and injury in an animal model of preterm infants

Anemia induces gut inflammation and injury in an animal model of preterm infants

Hypoxia-inducible factors: key regulators of myeloid cells during inflammation

Hif-1α regulates macrophage-endothelial interactions during blood vessel development in zebrafish

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