Loss of Smad4 drives vascular malformations via c-KIT-dependent high shear stress mimicry

Deviations above or below this threshold trigger adaptive remodeling to restore physiological shear levels. Disruption of this control mechanism leads to enlarged arterial-venous malformations (AVMs) in hereditary haemorrhagic telangiectasia (HHT), a vascular disorder caused by heterozygous loss-of-function (LOF) mutation in ALK1, ENG or SMAD4.

Mechanistically, Smad4 deficient ECs are reset to a lower FSS set point value, resulting in AVMs that show characteristics of high FSS remodeling with elevated Klf4 and excessive activation of the downstream Akt. Here, we investigated the Klf4-Akt upstream mechanisms by which Smad4 sets the physiological FSS setpoint. We identified the receptor tyrosine kinase c-Kit as a novel component and regulator of the junctional mechanosensory receptor complex, which is highly upregulated in murine and human AVMs.