American journal of translational research · 2026
GDF15 predisposes aortic dissection through regulation of vascular smooth muscle cell proliferation and phenotypic change via the ERK/Akt pathway.
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Tan Qian, Yang Zhijie, Zhang Jianjun
Аннотация
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.
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.