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 independent manner, possibly reliant on the blood vessel origin (artery and vein) of endothelial cells. Given that the AhR signaling pathway has the broader 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.

Differential Distribution of Tryptophan-Metabolites in Fetal and Maternal Circulations During Normotensive and Preeclamptic Pregnancies

“…S1) [39] in placentas. Trp-metabolites are important in regulating maternal and fetal cell function during pregnancy [8][9][10]40]. This is further supported by our current findings that Kyn and ILA differentially regulate cell viability and monolayer integrity in HUVECs.…”

“…To date, it remains to be investigated how Kyn and ILA induce these cellular responses in HUVECs. However, as both Kyn and ILA are aryl hydrocarbon receptor (AhR, a ligand-activated transcription factor) ligands [8,9,39,44], their actions might be mediated via the AhR signaling pathway [40,44].…”

“…It is worthy noting that many additional Trp-metabolites such as 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester and indole-3-carbinol derivatives [40,44] may be present and function during pregnancy. Further research is required to dissect the roles of these Trp-metabolites in pregnancy.…”

Aryl Hydrocarbon Receptor and Cysteine Redox Dynamics Underlie (Mal)adaptive Mechanisms to Chronic Intermittent Hypoxia in Kidney Cortex

“…To address the effect of cysteine and cystine on both AhR and its downstream target gene CYP1A1, gene expression was evaluated in HUVEC cells exposed to a range of Cys and cystine concentrations using early (6 h) and late (24 h) timepoints. Both AhR [ 45 ] (reviewed in [ 46 ]) and oxidized cysteine [ 47 , 48 ] (reviewed in [ 31 ]) have been described to impact endothelial cells, promoting toxicity to the cardiovascular system. This knowledge supported the selection of HUVECs for this proof-of-concept study of the interplay between cysteine redox changes and AhR.…”

Expression of Pro-Angiogenic Markers Is Enhanced by Blue Light in Human RPE Cells

“…AHR encodes for the aryl hydrocarbon receptor, a transcription factor that inhibits transcription of pro-angiogenic genes. Oxidative stress reduced AHR expression leading to endothelial cell proliferation [ 57 ]. Moreover, in endothelial barriers, AHR was shown to contribute to the maintenance of barrier properties by mediating cytochrome CYP1 expression, in response to xenobiotics [ 58 ].…”