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SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations
Kuheli Banerjee, … , Martin A. Schwartz, Roxana Ola
Kuheli Banerjee, … , Martin A. Schwartz, Roxana Ola
Published July 25, 2023
Citation Information: J Clin Invest. 2023;133(18):e168352. https://doi.org/10.1172/JCI168352.
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Research Article Vascular biology Article has an altmetric score of 1

SMAD4 maintains the fluid shear stress set point to protect against arterial-venous malformations

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Abstract

Vascular networks form, remodel, and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with bone morphogenic proteins 9 and 10 (BMP9 and BMP10). Conversely, mutation of the BMP receptors activin-like kinase 1 (ALK1), endoglin (ENG), or the downstream effector, SMAD family member 4 (SMAD4) leads to hereditary hemorrhagic telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). How endothelial cells (ECs) integrate FSS and BMP signals in vascular development and homeostasis and how mutations give rise to vascular malformations is not well understood. Here, we aimed to elucidate the mechanism of synergy between FSS and SMAD signaling in vascular stability and how disruption of this synergy leads to AVMs. We found that loss of Smad4 increased the sensitivity of ECs to flow by lowering the FSS set point, with resulting AVMs exhibiting features of excessive flow-mediated morphological responses. Mechanistically, loss of SMAD4 disinhibits flow-mediated KLF4-TIE2-PI3K/Akt signaling, leading to cell cycle progression–mediated loss of arterial identity due to KLF4-mediated repression of cyclin dependent Kinase (CDK) inhibitors CDKN2A and CDKN2B. Thus, AVMs caused by Smad4 deletion are characterized by chronic high flow remodeling with excessive EC proliferation and loss of arterial identity as triggering events.

Authors

Kuheli Banerjee, Yanzhu Lin, Johannes Gahn, Julio Cordero, Purnima Gupta, Islam Mohamed, Mariona Graupera, Gergana Dobreva, Martin A. Schwartz, Roxana Ola

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Figure 5

Flow-induced KLF4 acts upstream of mechanosensory complex PI3K/Akt.

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Flow-induced KLF4 acts upstream of mechanosensory complex PI3K/Akt.
(A) ...
(A) Western Blot (WB) for pAkt, Akt, and SMAD4 of HUVECs transfected with CTRL or SMAD4 siRNAs grown in static or subject to 1, 5, and 12 DYNES/cm2 for 4 hours. (B) Quantifications of pAkt levels normalized to total Akt for the indicated conditions (n = 3/group). (C) WB for pAkt, total Akt, PECAM, and GAPDH of CTRL, SMAD4, KLF4, and SMAD4;KLF4 siRNAs HUVECs subjected to 12 DYNES/cm2 for 4 hours. (D) Quantification of pAkt/Akt (n = 6/group) and PECAM/GAPDH (n = 3/group) in the indicated genotypes. (E) WB for pAkt, total Akt, PECAM, and GAPDH in CTRL-OE and KLF4-OE cells grown in static versus 12 DYNES/cm2 for 4 hours. (F) Quantification of pAkt/Akt and PECAM/GAPDH in the indicated genotypes (n = 3/group). (G) Anti-phosphoS6 (pS6) (white-upper panel) and colabeling for pS6 (white) and IB4 (red) (lower panel) of retinal flat mounts from Tx-induced P6 fl/fl, Smad4iΔEC, Klf4iΔEC, and Smad4;Klf4iΔEC. Green and yellow arrowheads indicate non-AVM regions and AVM regions, respectively. (H) Quantification of pS6 levels in the vascular plexus of fl/fl, Smad4iΔEC (in regions free of AVMs and within the AVMs), Klf4iΔEC, and Smad4;Klf4iΔEC (n = 6 [2 images/retina]/group). a, artery; v, vein. Scale bars: 50μm in G. Mann-Whitney test (B), 1-way Anova (D, F, and H) were used to determine statistical significance. Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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