Biochimica et biophysica acta. Molecular basis of diseaseJul 4, 2025

GALNT4 may influence aortic dissection by changing blood vessel muscle cell behavior through TGF-beta/smad signaling

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

GALNT4 expression is significantly elevated in the arteries of human aortic dissection patients and murine models (P < 0.01).

Knockdown of GALNT4 in smooth muscle cells reduced aortic dissection incidence from 76.9% to 53.8% and rupture rates from 70.0% to 28.6%.
Higher GALNT4 levels in vascular smooth muscle cells were observed in both human and mouse aortic dissection tissues compared to normal arteries.
GALNT4 knockdown improved aortic dissection pathology by preserving contractile markers and suppressing synthetic markers in mice.
In vitro knockdown of GALNT4 inhibited the migration and phenotypic switching of human aortic smooth muscle cells induced by Ang II.
GALNT4 knockdown reduced a specific type of protein modification on TGF-βR2, which then inhibited the activation of downstream signaling pathways.

Simplified

Aortic dissection (AD) is a life-threatening vascular disorder whose underlying molecular mechanisms remain poorly understood. Polypeptide N-acetylgalactosaminyltransferase 4 (GALNT4), an enzyme that transfers N-acetylgalactosamine (GalNAc) to serine and threonine residues on target proteins, has been implicated in the development of cardiovascular diseases. However, its specific role in AD remains unclear. This study analyzed GALNT4 expression in human AD tissues and murine AD models induced by β-aminopropionitrile (BAPN) and angiotensin II (Ang II). Results revealed significantly elevated GALNT4 expression in the arteries of both human AD patients and AD mice (P < 0.01). Specifically, GALNT4 levels in vascular smooth muscle cells (VSMCs) from human and mouse AD arteries were markedly higher than in normal arteries. Smooth muscle cell (SMC)-specific knockdown of GALNT4 reduced AD incidence (53.8 % vs. 76.9 %) and rupture rates (28.6 % vs. 70.0 %), while improving AD pathology. This improvement was characterized by preserved contractile markers (α-SMA, SM22α) and suppressed synthetic markers (OPN, MMP2/9) in mice. In vitro, GALNT4 knockdown inhibited Ang II-induced phenotypic switching and migration of human aortic SMCs (29 % vs. 41 %, P < 0.01), whereas GALNT4 overexpression reversed these effects. Mechanistically, GALNT4 knockdown reduced O-GalNAcylation of TGF-βR2, inhibiting Smad2/3 phosphorylation and consequently blocking downstream Smad signaling pathway activation. In conclusion, GALNT4 regulates VSMC phenotypic switching and dysfunction through glycosylation-dependent activation of the TGF-β/Smad signaling pathway, positioning it as a potential therapeutic target for AD intervention.

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Declaration of competing interest The manuscript has been read and approved by all authors for publication. It has not been published or is not being considered for publication elsewhere, in whole or part, in any language.

PubMed

GALNT4 may influence aortic dissection by changing blood vessel muscle cell behavior through TGF-beta/smad signaling

Abstract

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