PIEZO1 overexpression in hereditary hemorrhagic telangiectasia arteriovenous malformations.

BACKGROUND

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function mutations in Activin receptor-like kinase 1 (ALK1) cause type 2 HHT and knockout (KO) mice develop AVMs due to overactivation of VEGFR2/PI3K/AKT signaling pathways. However, the full spectrum of signaling alterations in mutants remains unknown and means to combat AVM formation in patients are yet to be developed.

METHODS

Single-cell RNA sequencing of endothelial-specific KO mouse retinas and controls identified a cluster of endothelial cells (ECs) that was unique to mutants and that overexpressed fluid shear stress (FSS) signaling signatures including upregulation of the mechanosensitive ion channel PIEZO1. PIEZO1 overexpression was confirmed in human HHT lesions, and genetic and pharmacological PIEZO1 inhibition was tested in KO mice, as well as downstream PIEZO1 signaling.

RESULTS

Pharmacological PIEZO1 inhibition, and genetic deletion in -deficient mice effectively mitigated AVM formation. Furthermore, we identified that elevated VEGFR2/AKT, ERK5-p62-KLF4, hypoxia and proliferation signaling were significantly reduced in - double ECKO mice.

CONCLUSIONS

PIEZO1 overexpression and signaling is integral to HHT2, and PIEZO1 blockade reduces AVM formation and alleviates cellular and molecular hallmarks of ALK1-deficient cells. This finding provides new insights into the mechanistic underpinnings of ALK1-related vascular diseases and identifies potential therapeutic targets to prevent AVMs.