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SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

ABSTRACT: BACKGROUND:Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin ( ENG) and activin-receptor-like kinase 1 ( AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-? (TGF?)/bone morphogenetic protein (BMP) family ligands that signal via activin-like kinase receptors (ALKs). Ligand-neutralizing antibodies or inducible, endothelial-specific Alk1 deletion induce AVMs in mouse models as a result of increased PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling. Here we addressed if SMAD4 was required for BMP9-ALK1 effects on PI3K/AKT pathway activation. METHODS:The authors generated tamoxifen-inducible, postnatal, endothelial-specific Smad4 mutant mice ( Smad4i?EC). RESULTS:We found that loss of endothelial Smad4 resulted in AVM formation and lethality. AVMs formed in regions with high blood flow in developing retinas and other tissues. Mechanistically, BMP9 signaling antagonized flow-induced AKT activation in an ALK1- and SMAD4-dependent manner. Smad4i?EC endothelial cells in AVMs displayed increased PI3K/AKT signaling, and pharmacological PI3K inhibitors or endothelial Akt1 deletion both rescued AVM formation in Smad4i?EC mice. BMP9-induced SMAD4 inhibited casein kinase 2 ( CK2) transcription, in turn limiting PTEN phosphorylation and AKT activation. Consequently, CK2 inhibition prevented AVM formation in Smad4i?EC mice. CONCLUSIONS:Our study reveals SMAD4 as an essential effector of BMP9-10/ALK1 signaling that affects AVM pathogenesis via regulation of CK2 expression and PI3K/AKT1 activation.

SUBMITTER: Ola R

PROVIDER: S-EPMC6309254 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

Ola Roxana R Künzel Sandrine H SH Zhang Feng F Genet Gael G Chakraborty Raja R Pibouin-Fragner Laurence L Martin Kathleen K Sessa William W Dubrac Alexandre A Eichmann Anne A

Circulation 20181101 21

<h4>Background</h4>Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder that causes arteriovenous malformations (AVMs). Mutations in the genes encoding Endoglin ( ENG) and activin-receptor-like kinase 1 ( AVCRL1 encoding ALK1) cause HHT type 1 and 2, respectively. Mutations in the SMAD4 gene are present in families with juvenile polyposis-HHT syndrome that involves AVMs. SMAD4 is a downstream effector of transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP ...[more]

PMID: 29976569

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Project description:BackgroundCerebral arteriovenous malformations (AVMs) are pathological connections between arteries and veins. Dual-venc 4D flow MRI, an extended 4D flow MRI method with improved velocity dynamic range, provides time-resolved 3D cerebral hemodynamics.PurposeTo optimize dual-venc 4D flow imaging parameters for AVM; to assess the relationship between spatial resolution, acceleration, and flow quantification accuracy; and to introduce and apply the flow distribution network graph (FDNG) paradigm for storing and analyzing complex neurovascular 4D flow data.Study typeRetrospective cohort study.Subjects/phantomScans were performed in a specialized flow phantom: 26 healthy subjects (age 41 ± 17 years) and five AVM patients (age 27-68 years).Field strength/sequenceDual-venc 4D flow with varying spatial resolution and acceleration factors were performed at 3T field strength.AssessmentQuantification accuracy was assessed in vitro by direct comparison to measured flow. FDNGs were used to quantify and compare flow, peak velocity (PV), and pulsatility index (PI) between healthy controls with various Circle of Willis (CoW) anatomy and AVM patients.Statistical testsIn vitro measurements were compared to ground truth with Student's t-test. In vivo groups were compared with Wilcoxon rank-sum test and Kruskal-Wallis test.ResultsFlow was overestimated in all in vitro experiments, by an average 7.1 ± 1.4% for all measurement conditions. Error in flow measurement was significantly correlated with number of voxels across the channel (P = 3.11 × 10-28 ) but not with acceleration factor (P = 0.74). For the venous-arterial PV and PI ratios, a significant difference was found between AVM nidal and extranidal circulation (P = 0.008 and 0.05, respectively), and between AVM nidal and healthy control circulation (P = 0.005 and 0.003, respectively).Data conclusionDual-venc 4D flow MRI and standardized FDNG analysis might be feasible in clinical applications. Venous-arterial ratios of PV and PI are proposed as network-based biomarkers characterizing AVM nidal hemodynamics.Level of evidence3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;50:1718-1730.

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SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

Publications

SMAD4 Prevents Flow Induced Arteriovenous Malformations by Inhibiting Casein Kinase 2.

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