The Role of Aryl Hydrocarbon Receptor in the Endothelium: A Systematic Review

Abstract

Activation of the aryl hydrocarbon receptor (AhR) has been shown to be important in physiological processes other than detoxification, including vascular homeostasis. Although AhR is highly expressed in the endothelium, its function has been poorly studied. This systematic review aims to summarise current knowledge on the AhR role in the endothelium and its cardiovascular implications. We focus on endogenous AhR agonists, such as some uremic toxins and other agonists unrelated to environmental pollutants, as well as studies using AhR knockout models. We conclude that AhR activation leads to vascular oxidative stress and endothelial dysfunction and that blocking AhR signalling could provide a new target for the treatment of vascular disorders such as cardiovascular complications in patients with chronic kidney disease or pulmonary arterial hypertension.

Keywords: AhR; aorta; cardiovascular system; endothelial function; endothelium; vascular homeostasis.

Figure 1

Schematic representation of the canonical and non-canonical signalling pathways of AhR. AhR is found in the cytosol in its latent form associated with a protein complex (HSP90: heat shock protein, XAP2: hepatitis B virus X-associated protein, SRC: Proto-Oncogene tyrosine-protein kinase s-Src and p23). After activation by ligands, it translocates to the nucleus and forms a heterodimer with AhR nuclear translocator (ARNT-), which acts as a transcriptional factor, increasing gene expression contained in the Xenobiotic response element (XRE). This is the canonical pathway and affects the expression of genes such as CYP1A1, CYP1B1, CYP1A2, AhR repressor (AhRR), or indoleamine 2,3-dioxygenase (IDO1). By non-canonical pathway, AhR binds other proteins such as pRB, NF-κB, c-Maf, or KLF6 and increases the expression of genes contained in the Non-consensus Xenobiotic response element (NC-XRE). Moreover, when AhR is activated by ligands, the release of c-Src (SRC) can activate epidermal growth factor receptor (EGFR) signalling. Finally, AhR is degraded by proteasome in the cytosol, which is one of the possible degradation pathways. Image created using BioRender.

Figure 2

Search flow diagram for systematic review.