GDF15 predisposes aortic dissection through regulation of vascular smooth muscle cell proliferation and phenotypic change via the ERK/Akt pathway.

OBJECTIVE

Aortic dissection (AD) represents a life-threatening vascular disorder characterized by abnormal vascular smooth muscle cell (VSMC) behavior and extracellular matrix remodeling. Growth differentiation factor 15 (GDF15) is a stress-related cytokine associated with the pathogenesis of cardiovascular diseases, but its exact role in AD remains to be elucidated.

METHODS

Human aortic smooth muscle cells (HASMCs) were incubated with angiotensin II (Ang II) to simulate an in vitro pathological tension environment. Gain- and loss-of-function experiments were carried out to investigate the functional role of GDF15 in regulating cell growth, migration, phenotypic transformation, and inflammatory reaction. The involvement of the ERK/protein kinase B (Akt) pathway was studied using a ERK inhibitor. Clinical significance was analyzed by detecting the plasma levels of GDF15 and matrix metalloproteinases (MMPs) in AD patients and healthy controls.

RESULTS

Ang II upregulated GDF15 expression in HASMCs in a dose- and time-dependent manner. GDF15 overexpression promoted HASMC proliferation, migration, and phenotypic switching from a contractile to a synthetic state, accompanied by increased expression of MMP-2 and MMP-9 and pro-inflammatory cytokines (TNF-α, IL-6, and MCP-1). GDF15 knockdown produced opposite effects. Mechanistically, GDF15 activated both ERK and Akt pathways; however, pharmacological inhibition experiments suggested that the pro-remodeling effects of GDF15 were primarily mediated through ERK signaling. Clinically, plasma concentrations of GDF15, MMP-2, and MMP-9 were significantly higher in AD patients compared with healthy controls.

CONCLUSIONS

GDF15 promotes aberrant remodeling of HASMCs by enhancing proliferation, migration, phenotypic transformation, and inflammatory responses via ERK-dependent signaling. Elevated plasma GDF15 levels in AD patients suggest that GDF15 can serve as a potential diagnostic biomarker and therapeutic target for AD.