The Mechanism of Matrilin-2 Inhibiting the Progression of In-Stent Restenosis for Lower Extremity Arteriosclerosis Obliterans via TGF-β/Smad Signaling Pathway.

Background: To evaluate differential expression of matrilin-2/transforming growth factor (TGF)-β/Smad signaling pathway components and downstream targets in primary atherosclerotic plaques versus in-stent restenosis (ISR) lesions of femoropopliteal arteries in lower extremity arteriosclerosis obliterans (LEASO) patients and to explore the mechanistic role of this pathway in regulating vascular smooth muscle cell (VSMC) phenotypic modulation for preventing postinterventional restenosis.

Methods: Femoropopliteal intimal tissues were collected from 20 primary LEASO patients and 20 ISR patients with matched baseline characteristics. Western blot quantified matrilin-2, TGF-β, contractile (TAGLN) versus synthetic (MYH10) VSMC markers, and Smad phosphorylation levels. Lentiviral transduction was used to overexpress matrilin-2 in human aortic VSMCs. Subsequent analyses included TGF-β/p-Smad signaling activation, VSMC phenotypic marker expression, and functional assessments of proliferation/migration.

Results: ISR lesions exhibited significantly reduced matrilin-2, TGF-β, and p-Smad levels compared to primary lesions, alongside elevated MYH10 and reduced TAGLN expression. Matrilin-2 overexpression upregulated TGF-β, TAGLN, and p-Smad, while suppressing VSMC proliferation and migration. Smad inhibition reversed these effects, increasing MYH10 and enhancing proliferative/migratory capacities.

Conclusion: ISR lesions demonstrate predominant synthetic VSMC phenotypes compared to primary LEASO plaques. Matrilin-2 inhibits the phenotypic transition from contractile to synthetic VSMC by upregulating TGF-β/Smad signaling, thereby attenuating postinterventional restenosis in LEASO.