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| Item Type: | Article |
|---|---|
| Title: | Loss of Smad4 drives vascular malformations via c-KIT–dependent high–fluid shear stress mimicry |
| Creators: |
Gahn, Johannes, Wu, Fan, Zhang, Qing, Di, Yuxi, Behera, Tanmaya, Ren, Yonggang, Hashemi, Zohrah, Banerjee, Kuheli, Cordero, Julio, Gherman, Claudia, Andorfer, Kornelia, Seebauer, Caroline T., Mirzapour-Shafiyi, Fatemeh, Dobreva, Gergana  ORCID: https://orcid.org/0000-0002-4814-9416, Schwartz, Martin A. and Ola, Roxana
|
| Abstract: | Vascular endothelial cells (ECs) encode a homeostatic fluid shear stress (FSS) set point that is essential for vascular stability. Deviations above or below this threshold trigger adaptive remodeling to restore physiological shear levels. Disruption of this control mechanism leads to enlarged arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia, 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 high activation of the downstream Akt. Here, we investigated the KLF4/Akt upstream mechanisms by which SMAD4 sets the physiological FSS set point. We identified the receptor tyrosine kinase c-KIT as a component and regulator of the junctional mechanosensory receptor complex, which is highly upregulated in murine and human AVMs. SMAD4 restrains flow signaling by limiting c-KIT–dependent ERK5 activation and KLF4 induction. Thus, SMAD4 LOF leads to sustained c-KIT engagement in the sensory junctional apparatus, driving enhanced and prolonged activation of the ERK5/KLF4/Akt signaling axis. These results show that Smad4-LOF mutations induce malformations by disabling a key homeostatic mechanism and identify c-KIT as a potentially previously unrecognized therapeutic target. |
| Keywords: | Arteriovenous Malformations, Endothelial Cells, Hereditary Hemorrhagic Telangiectasia, Knockout Mice, Kruppel-Like Factor 4, Loss of Function Mutation, Mechanical Stress, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-kit, Smad4 Protein, Animals, Mice |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 136 |
| Number: | 19 |
| Page Range: | e197609 |
| Date: | 1 October 2026 |
| Official Publication: | https://doi.org/10.1172/jci197609 |
| PubMed: | View item in PubMed |
| Related to: |
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