Giant cell arteritis: Hypoxia pathways may contribute to disease chronicity

2018 edition

Roser Alba-Rovira

Giant-cell arteritis (GCA) is an inflammatory disease of blood vessels. This inflammation is due to an unknown error of the immune system that causes a chronic inflammation in the arteries. GCA mostly affects medium and large vessels and is the most frequent vasculitis in Europe and North America. It affects about 1 in 15,000 people over the age of 50 years and females are more often affected than males. Symptoms may include headache, flu-like symptoms, double vision, and difficulty opening the mouth. Complication can include blockage of the artery to the eye with resulting blindness, aortic dissection, and aortic aneurysm. Currently patients are treated with corticosteroids that have many secondary effects. The gold standard to diagnose GCA is a temporal artery biopsy (TAB).

Vascular response to inflammation leads to arterial remodeling and occlusion with compensatory angiogenesis. Hypoxia Inducible Factor (HIF) 1 is a protein present in the nucleus of the cells that help them survive without oxygen. This protein is present in hypoxia conditions. HIF1 upregulates the expression of multiple gene involved in inflammation, angiogenesis and fibrosis, three mechanisms found in GCA. Therefore, the aim of this project is to study the expression and function of HIF1 in GCA.

mRNAs of interest were assessed by quantitative real-time RT-PCR in fresh-frozen temporal arteries from 29 GCA patients and 29 controls. Fresh arteries from GCA patients and controls were also cryopreserved for immunofluorescence and evaluated by confocal microscopy. Human temporal artery derived VSMC were cultured with recombinant cytokines (R&D systems) or co-cultured with peripheral blood mononuclear cells (PBMCs) mimicking vascular inflammation.

HIF1α mRNA was increased in GCA compared with control arteries. The major cell type expressing HIF1α was VSMC, both in GCA and in control arteries. Co-culture of VSMC with PBMC markedly increased HIF1α expression by VSMC and promoted nuclear localization in normoxia conditions. Consistently, cytokines known to be present in GCA and also present in the co-culture supernatant such as IL-6, IL-1β and TNFα, increased HIF1α expression by VSMC.  In vitro stabilization of HIF1α in VSMC by CoCl2 resulted in increased expression of angiogenic factors (VEGF and its receptor), metalloproteinases (MMP-9), pro-inflammatory cytokines (IL-1β and IL-6) and adhesion molecules (ICAM-1 and VCAM-1).