Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

Han, Yong Seop; Tao, Jiayi; Gomer, Alla; Ramírez-Bergeron, Diana L.

doi:10.1177/1358863x14559588

Cited by 7 publications

(8 citation statements)

References 69 publications

(135 reference statements)

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“…To explore the role of ecARNT in angiogenesis during diabetes, we conducted a series of studies in mice carrying a tamoxifen-inducible, EC-specific ARNT-knockout ( Arnt Δ EC, ERT2 ) mutation. The mutant line was generated by breeding Arnt flox/flox mice in which exon 6 of Arnt is flanked by loxP sequences ( Wu et al, 2014 ), with VE-cadherin-Cre ERT 2 mice expression of Cre-recombinase is tamoxifen-inducible and regulated by the vascular endothelial (VE) Cadherin promoter ( Han et al, 2014 ; Okabe et al, 2014 ; Figure 1C ). After cross-breeding for two generations, PCR analyses of genomic DNA confirmed that the Arnt Δ EC, ERT2 genotype was present in ∼1/4 of offspring ( Figure 1D ), and in the absence of tamoxifen treatment, the mice were phenotypically indistinguishable from wild-type mice.…”

Section: Resultsmentioning

confidence: 99%

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

Nguyen

Zheng

Knapp

et al. 2021

Front. Cell Dev. Biol.

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Hypoxia-inducible factors (HIFs) are the master regulators of angiogenesis, a process that is impaired in patients with diabetes mellitus (DM). The transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT, also known as HIF1β) has been implicated in the development and progression of diabetes. Angiogenesis is driven primarily by endothelial cells (ECs), but both global and EC-specific loss of ARNT-cause are associated with embryonic lethality. Thus, we conducted experiments in a line of mice carrying an inducible, EC-specific ARNT-knockout mutation (ArntΔEC, ERT2) to determine whether aberrations in ARNT expression might contribute to the vascular deficiencies associated with diabetes. Mice were first fed with a high-fat diet to induce diabetes. ArntΔEC, ERT2 mice were then adminstrated with oral tamoxifen to disrupt Arnt and peripheral angiogenesis was evaluated by using laser-Doppler perfusion imaging to monitor blood flow after hindlimb ischemia. The ArntΔEC, ERT2 mice had impaired blood flow recovery under both non-diabetic and diabetic conditions, but the degree of impairment was greater in diabetic animals. In addition, siRNA-mediated knockdown of ARNT activity reduced measurements of tube formation, and cell viability in human umbilical vein endothelial cells (HUVECs) cultured under high-glucose conditions. The ArntΔEC, ERT2 mutation also reduced measures of cell viability, while increasing the production of reactive oxygen species (ROS) in microvascular endothelial cells (MVECs) isolated from mouse skeletal muscle, and the viability of ArntΔEC, ERT2 MVECs under high-glucose concentrations increased when the cells were treated with an ROS inhibitor. Collectively, these observations suggest that declines in endothelial ARNT expression contribute to the suppressed angiogenic phenotype in diabetic mice, and that the cytoprotective effect of ARNT expression in ECs is at least partially mediated by declines in ROS production.

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Section: Resultsmentioning

confidence: 99%

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

Nguyen

Zheng

Knapp

et al. 2021

Front. Cell Dev. Biol.

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“…This negative interaction between the AhR and hypoxia signaling pathways appears to depend at least in part on the availability of ARNT. Furthermore, it has been shown that ARNT KO mice exhibit vascular and angiogenic impairments that can contribute to impaired migration of immune cells during the first stages of wound healing (40). This negative interaction has been observed in liver (41,42) and, unlike the study of Pollenz et al…”

Section: Impaired Wound Healingmentioning

confidence: 96%

The aryl hydrocarbon receptor pathway plays a central role in the cutaneous response to pollutants

2022

European Journal of Dermatology

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…The essential role of HIF‐1 in wound healing has been confirmed by the impaired angiogenesis, decreased EPC recruitment, and delayed wound healing exhibited in heterozygous HIF‐1α knockout mice and in aged mice with reduced HIF‐1α expression . Wound healing defects are also present in mice in which HIF‐1β has been specifically inactivated in endothelial cells .…”

Section: Roles Of Hypoxia and Hypoxia‐inducible Factor‐1 (Hif‐1) In Wmentioning

confidence: 99%

Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers

Catrina

Zheng

2016

Diabetes Metabolism Res

111

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Diabetic foot ulceration (DFU) is a chronic complication of diabetes that is characterized by impaired wound healing in the lower extremities. DFU remains a major clinical challenge because of poor understanding of its pathogenic mechanisms. Impaired wound healing in diabetes is characterized by decreased angiogenesis, reduced bone marrow-derived endothelial progenitor cell (EPC) recruitment, and decreased fibroblast and keratinocyte proliferation and migration. Recently, increasing evidence has suggested that increased hypoxic conditions and impaired cellular responses to hypoxia are essential pathogenic factors of delayed wound healing in DFU. Hypoxia-inducible factor-1 (HIF-1, a heterodimer of HIF-1α and HIF-1β) is a master regulator of oxygen homeostasis that mediates the adaptive cellular responses to hypoxia by regulating the expression of genes involved in angiogenesis, metabolic changes, proliferation, migration, and cell survival. However, HIF-1 signalling is inhibited in diabetes as a result of hyperglycaemia-induced HIF-1α destabilization and functional repression. Increasing HIF-1α expression and activity using various approaches promotes angiogenesis, EPC recruitment, and granulation, thereby improving wound healing in experimental diabetes. The mechanisms underlying HIF-1α regulation in diabetes and the therapeutic strategies targeting HIF-1 signalling for the treatment of diabetic wounds are discussed in this review. Further investigations of the pathways involved in HIF-1α regulation in diabetes are required to advance our understanding of the mechanisms underlying impaired wound healing in diabetes and to provide a foundation for developing novel therapeutic approaches to treat DFU.

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Loss of endothelial-ARNT in adult mice contributes to dampened circulating proangiogenic cells and delayed wound healing

Cited by 7 publications

References 69 publications

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

Endothelial Aryl Hydrocarbon Receptor Nuclear Translocator Mediates the Angiogenic Response to Peripheral Ischemia in Mice With Type 2 Diabetes Mellitus

The aryl hydrocarbon receptor pathway plays a central role in the cutaneous response to pollutants

Disturbed hypoxic responses as a pathogenic mechanism of diabetic foot ulcers

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