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Loss of Smad4 drives vascular malformations via c-KIT-dependent high shear stress mimicry

GSE330070 Homo sapiens (human) RNA-seq (gene expression) 24 samples Submitted 2026/05/11 Platform GPL23227
At a glance

RNA-seq (gene expression) · human · 24 samples

What it is
RNA-seq (gene expression)Gene activity measured by sequencing. The summary does not mention single-cell work, so this is most likely bulk: one average per sample, the usual starting point for comparing groups.
Organism
Homo sapiens (human)
Samples
24 samples: 8 conditions, mostly in triplicateGroups are read from the sample names, not from the paper. Check the list below.
Data you can get
A processed table (series matrix) and supplementary files from NCBI; the raw sequencing reads from ENA. Which of these hold counts depends on the study, so check the file list.
Summary (written by the submitters)
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 arterial-venous malformations (AVMs) in hereditary haemorrhagic telangiectasia (HHT), a vascular disorder caused by heterozygous loss-of-function (LOF) mutation in ALK1, ENG or SMAD4.
Read the full summary ↓
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 excessive activation of the downstream Akt. Here, we investigated the Klf4-Akt upstream mechanisms by which Smad4 sets the physiological FSS setpoint. We identified the receptor tyrosine kinase c-Kit as a novel 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 excessive 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 novel therapeutic target.
This dataset
Open GSE330070 in finder → Find more human RNA-seq datasets →
Download · which file do I need?

Direct links to NCBI and ENA, no account and no request form. Pick by what you want to do: take the small processed table to look, the supplementary files to re-analyse, or the original raw data to start over.

1 · Just have a look

Processed table

The series matrix: one table of values per sample as the submitters processed it. The smallest download, and it opens in Excel or R. Start here to see what the data look like.

Series matrix ↓
2 · Re-analyse it

Supplementary files

The count tables and other files the authors uploaded. Take only the samples you need, or the whole study as GSE330070_RAW.tar (it can run to tens of gigabytes).

All supplementary files ↗ Whole study · RAW.tar ↓
3 · Start from the raw reads

Raw sequencing reads

The original FASTQ files, straight from the sequencer, held at ENA. Large, and you align them yourself, so only choose this if you need to re-process the study from scratch.

Raw reads on ENA ↗

What the files usually look like: For RNA-seq the counts are usually a table among the supplementary files (look for 'counts', 'expression', 'FPKM' or 'TPM' in the file name). The series matrix of a sequencing study is sometimes nearly empty.

Also filed as BioProject PRJNA1462696 and SRA study SRP697946. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗
Study design
8 conditions, mostly in triplicate
HUVECs, siControl, static, ×3 HUVECs, siControl, 1dynes/cm2 for 2h, ×3 HUVECs, siControl, 5dynes/cm2 for 2h, ×3 HUVECs, siControl, 12dynes/cm2 for 2h, ×3 HUVECs, siSMAD4, static, ×3 HUVECs, siSMAD4, 1dynes/cm2 for 2h, ×3 HUVECs, siSMAD4, 5dynes/cm2 for 2h, ×3 HUVECs, siSMAD4, 12dynes/cm2 for 2h, ×3

Supports a between-group comparison across 24 samples.

How we read this: 8 replicated groups read from 24 sample titles; they account for 24 of them. These groups are guessed from the sample names, not taken from the paper, so check them against the sample list below before relying on them.

Samples in this study
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