GALNT4 controls aortic dissection by regulating vascular smooth muscle cell phenotype switch and dysfunction through the TGF-β/smad signaling.

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.