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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 7

Smad4 LOF blocks flow-mediated cell cycle arrest resulting in loss of arterial identity.

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Smad4 LOF blocks flow-mediated cell cycle arrest resulting in loss of a...
(A) Significantly changed GO terms in CTRL versus SMAD4 siRNAs HUVECs subject to 12 DYNES/cm2. n = 3/group. (B) Heatmap for the expression of cell cycle regulators in CTRL versus SMAD4 siRNAs HUVECs grown in static and subject to 12DYNES/cm2 (n = 3/group). Color key shows log2 changes. (C) qPCR for CCNB1, CCNB2, CDK1, CDKN2A, and CDKN2B in CTRL versus SMAD4 siRNAs HUVECs grown in static versus subject to 12DYNES/cm2 (n = 3/group). (D and E) qPCR for CCNB1, CCNB2, CDK1, CDKN2A, and CDKN2B (D) and for EFNB2, SOX17, CX37, CX40, and CX43 (E) in KLF4 siRNAs and KLF4 OE as fold change in relation to CTRL siRNA and CTRL-OE HUVECs (n = 5–10/group). (F and H) Representative confocal images of labeled retinas for EphrinB2 (white) (F), SOX17 (white) (H) and IB4 (red) from Tx induced P6 fl/fl, Smad4iΔEC, Klf4iΔEC, and Smad4;Klf4iΔEC mice. (G and I) Quantification of EphrinB2 (G) and SOX17 (I) signals in the vascular plexus from the indicated genotypes (n = 4 retinas/group). (J) qPCR for EFNB2, SOX17, CX37, CX40, and CX43 in KLF4 OE and Palbociclib treated HUVECs (n = 5–6/group). Scale Bars: 100μm in F and H. a, artery; v, vein. Mann Whitney test (D and E) and 1-way Anova (C,G,I,J) 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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