Hypoxia inducible factors in hereditary hemorrhagic telangiectasia – analysis of human and murine models

Introduction Mutations in genes (especially ALK-1 and endoglin) whose encoded proteins are involved in the transforming growth factor β (TGF-β) family signaling lead to hereditary hemorrhagic telangiectasia, a rare disease of vascular endothelial cells. Hypoxia inducible factors (HIF) are known to interact with TGF-β signaling pathway and have an influence on angiogenesis. The aim of this study was to understand HIF regulation in patients with HHT.

Methods Within this study, HIF and their up- and downstream-regulated genes were analyzed in whole blood samples from patients with HHT as well as in organs from HHT simulating knockout-mice.

Results In total, 66 patients with HHT and 26 healthy controls were included in this study. The analysis revealed a significant lower expression of HIF-1 alpha (α) mRNA in patients with HHT compared to the healthy controls (p< 0.01). There was no correlation between the measured epistaxis severity (Epistaxis Severity Score, ESS) and HIF-1α expression (p >0.05). Genes upstream from HIF-1α in the inflammation response (e.g. nuclear factor kappa-light-chain-enhancer of activated B-cells; NFκB) were unchanged (p>0.05), whereas HIF-1α target genes were partly significant downregulated (e.g. interleukin 6; p<0.01). Reflecting human samples, organs of HHT-mice (n=17) showed decreased HIF-1α in intestine, lung and brain on protein level compared to wildtype siblings (n=14).

Conclusion Compared to healthy controls a reduced HIF-1α protein accumulation was seen in human and murine HHT models.Further studies have to clarify the mechanisms behind these interesting findings. Moreover, investigations may identify HIF-stabilization as a possible therapeutic target in HHT patients.

Publication History

Article published online:
24 May 2022