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Distinct endothelial pathomechanisms drive arterio-venous malformation in Alk1 or Smad4 loss-of-function conditions

ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal dominant disorder associated with mutations in the bone morphogenetic protein (BMP) pathway. Inherited heterozygous loss of function mutations and acquired loss of heterozygosity in either Alk1, Eng, or Smad4 lead to the development of arteriovenous malformations (AVMs), which trigger local vessel instability, hypoxia and vessel leakage or rupture. Current models assume common cellular pathomechanisms culminating in altered endothelial cell (EC) shape regulation, directional migration and proliferation control as a consequence of deficient BMP pathway signaling in ECs under the influence of blood-flow mediated shear stress. Here we report that loss of Alk1 or Smad4 surprisingly triggers very distinct endothelial phenotypes, signaling dynamics and transcriptional changes in ECs, both in vitro and in vivo. EC behavior in both in vivo and mosaic flow cultures illustrate that cells deficient in Smad4 effectively migrate against the direction of fluid shear, from veins to arteries, whereas cells lacking Alk1 fail to polarize and migrate against flow. Our data suggest that AVMs triggered by Smad4 mutations occur through hyperpruning of capillaries, thus precipitating flow in a single shunt, whereas AVMs caused by Alk1 mutation grow by cell accumulations close to the vein, as well as the persistence of a hyperdense plexus that drives nidus formation. We propose that the cellular pathomechanisms leading to AVM formation are not the same if the upstream BMP receptor Alk1, or the downstream common transcription factor Smad4 are mutated, raising the prospect for urgently needed, mechanism-based, therapeutic avenues that need to be tailored to correcting the specific pathomechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282952 | GEO | 2025/02/18

REPOSITORIES: GEO

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Project description:Purpose: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by arteriovenous malformations (AVMs). Over 90% of HHT patients carry heterozygous loss-of-function mutations in Transforming Growth Factor-beta (TGFb) signaling components activin receptor-like kinase 1 (ACVRL1/ALK1), endoglin (ENG), or mothers against decapentaplegic homolog 4 (SMAD4). Brain AVMs can be lethal for HHT patients. Here, we use an inducible endothelial (EC)-specific mouse line to investigate brain AVMs characteristics in Alk1-, Eng-, and Smad4-HHT mouse models. Angiopientin-2 (Ang2) inhibition diminishes HHT associated cerebral vascular defects. We aim to identify the shared transcriptional changes in brain ECs between these three HHT types, and provide insights for transcriptional changes upon Ang2 inhibition. Methods: ECs were isolated from brains of both WT and HHT mutant mice at postnatal day 7 (P7) for Smad4 and Eng models, P6 for Alk1 model. Total RNA was extracted from isolated brain ECs and quantified using Qubit RNA High Sensitivity Assay Kit. RNA integrity was determined using the Bioanalyzer RNA 6000 Nano assay kit. RNA library construction was performed with the TruSeq RNA Library Prep Kit v2 from Illumina. The resulting mRNA library was quantified using Qubit dsDNA High Sensitivity Assay Kit and verified using the Bioanalyzer DNA1000 assay kit. Verified samples were sequenced using the NextSeq 500/550 High Output Kit v2.5 (150 Cycles) on a Nextseq 550 system. Sequenced reads were aligned to the mouse (mm10) reference genome with RNA-seq alignment tool (version 2.0.1). The aligned reads were used to quantify mRNA expression and determine differentially expressed genes using the RNA-seq Differential Expression tool (version 1.0.1). Both alignment and differential expression analysis were performed using the tools in the BaseSpace Sequence Hub. Results: We identified 5509, 5381, and 2663 differentially expressed genes in Smad4, Alk1, and Eng HHT models respectively. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model. Conclusions: A common but unique pro-angiogenic program among all HHT models included 14 consistent upregulated and 5 consistent downregulated angiogic genes. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model.

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Distinct endothelial pathomechanisms drive arterio-venous malformation in Alk1 or Smad4 loss-of-function conditions

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