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Roles of aryl hydrocarbon receptor in endothelial angiogenic responses†.

ABSTRACT: Aryl hydrocarbon receptor (AhR) is a transcription factor, which can be activated by a plethora of structure-diverse ligands. Historically, AhR is known for its involvements in regulation of metabolism of xenobiotics. However, normal physiological roles of AhR have been defined in other essential biological processes, including vascular growth and function, reproduction, and immunoresponses. In contrast, aberrant expression and activation of the AhR signaling pathway occur in a variety of human diseases, many of which (e.g., preeclampsia, atherosclerosis, and hypertension) could be associated with endothelial dysfunction. Indeed, emerging evidence has shown that either exogenous or endogenous AhR ligands can induce endothelial dysfunction in either an AhR-dependent or AhR-independent manner, possibly reliant on the blood vessel origin (artery and vein) of endothelial cells. Given that the AhR signaling pathway has broad impacts on endothelial and cardiovascular function, AhR ligands, AhR, and their downstream genes could be considered novel therapeutic targets for those endothelial-related diseases. This review will discuss the current knowledge of AhR's mediation on endothelial function and potential mechanisms underlying these actions with a focus on placental endothelial cells.

SUBMITTER: Li Y

PROVIDER: S-EPMC7731988 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Roles of aryl hydrocarbon receptor in endothelial angiogenic responses†.

Li Yan Y Zhou Chi C Lei Wei W Wang Kai K Zheng Jing J

Biology of reproduction 20201001 5

Aryl hydrocarbon receptor (AhR) is a transcription factor, which can be activated by a plethora of structure-diverse ligands. Historically, AhR is known for its involvements in regulation of metabolism of xenobiotics. However, normal physiological roles of AhR have been defined in other essential biological processes, including vascular growth and function, reproduction, and immunoresponses. In contrast, aberrant expression and activation of the AhR signaling pathway occur in a variety of human ...[more]

PMID: 32716482

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Project description: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 (Arnt Δ EC, 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. Arnt Δ EC, 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 Arnt Δ EC, 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 Arnt Δ EC, 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 Arnt Δ EC, 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.

Dataset Information

Roles of aryl hydrocarbon receptor in endothelial angiogenic responses†.

Publications

Roles of aryl hydrocarbon receptor in endothelial angiogenic responses†.

Similar Datasets

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