c-KIT expands the tool kit for treating arteriovenous malformation
Ruilin Wu, Jason E. Fish
Ruilin Wu, Jason E. Fish
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Commentary

c-KIT expands the tool kit for treating arteriovenous malformation

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is characterized by fragile, enlarged vessels with arteriovenous connections, which can form arteriovenous malformations (AVMs) that are prone to rupture. It is driven by mutations in TGF‑β pathway genes that disrupt endothelial cell responses and blood vessel remodeling. Two studies published in this issue of the JCI identify c‑KIT as a central mediator of HHT vascular pathology. Gahn et al. showed that SMAD4 loss derepressed c‑KIT, whose activity in the junctional mechanosensory receptor complex of endothelial cells reset the fluid shear stress set point to drive maladaptive vascular remodeling. Drapé et al. demonstrated that ALK1 loss in a mouse model of HHT induced a regional pro‑angiogenic c‑KIT+ endothelial state in brain AVMs. Both studies showed that pharmacologic c-KIT inhibition mitigated disease, revealing an unexpected, potentially ligand‑independent role for c‑KIT and highlighting a promising therapeutic target.

Authors

Ruilin Wu, Jason E. Fish

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Figure 1

c-KIT as a mechanosensory component driving sustained outward remodeling and angiogenesis in HHT.

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c-KIT as a mechanosensory component driving sustained outward remodeling...
Under physiological conditions, c-KIT expression in the endothelium is low, and c-KIT signaling is dispensable for blood flow responses and vascular development. However, related studies by Drapé et al. (6) and Gahn et al. (5) report that in the setting of HHT, loss of ALK1 or SMAD4 expression led to c-KIT upregulation and incorporation into the junctional mechanosensory complex. This resulted in excessive junctional signaling, leading to a lowered fluid shear stress set point in HHT ECs and sustained endothelial activation through the MEKK3/MEK5/ERK5/KLF4/AKT signaling axis. HHT ECs with high levels of c-KIT activity showed altered EC morphology and alignment, increased proliferation, and unique angiogenic signatures, driving continuous pathological vascular remodeling. Inhibition of c-KIT signaling in pathological ECs may restore these altered endothelial flow responses, offering a potential therapeutic direction for the management of AVMs in HHT.