PIEZO1 Overexpression in Hereditary Hemorrhagic Telangiectasia Arteriovenous Malformations.

Abstract

Hereditary hemorrhagic telangiectasia is an inherited vascular disorder characterized by arteriovenous malformations (AVMs). Loss-of-function variations in activin receptor-like kinase 1 (<i>ALK1</i>) cause type 2 hereditary hemorrhagic telangiectasia, and <i>Alk1</i> knockout mice develop AVMs, along with overactivation of vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. The full spectrum of signaling alterations resulting from <i>ALK1</i> variations remains unknown, and more effective and specific inhibitors to combat AVM formation in patients are needed. Single-cell RNA sequencing of endothelial-specific <i>Alk1</i> knockout mouse retinas and controls was performed. Overexpression of fluid shear stress signaling signatures including the mechanosensitive ion channel PIEZO1 was confirmed in mouse and human type 2 hereditary hemorrhagic telangiectasia lesions. Genetic and pharmacological PIEZO1 inhibition was tested in <i>Alk1</i> knockout mice, along with downstream PIEZO1 signaling. A cluster of <i>Alk1</i> mutant endothelial cells with altered arterio-venous identity overexpressed pathways related to fluid shear stress, hypoxia, inflammation, cell cycle, and vascular endothelial growth factor receptor 2/phosphoinositide 3-kinase/AKT signaling. <i>Piezo1</i> deletion and pharmacological inhibition in <i>Alk1</i>-deficient mice mitigated AVM formation, whereas <i>Piezo1</i> overexpression enhanced AVM formation induced by ALK1 ligand blockade. Mechanistically, PIEZO1 inhibition reduced elevated vascular endothelial growth factor receptor 2/AKT, ERK5-p62-KLF4, endothelial nitric oxide synthase, hypoxia, proliferation, and inflammation in ALK1-deficient endothelium. PIEZO1 expression and signaling are elevated in type 2 hereditary hemorrhagic telangiectasia. 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.