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bioRxiv · 10.1101/2025.08.27.672378

Matrix metalloproteinase-3 promotes arteriovenous fistula failure by regulating FAK-AKT signaling

Xie, Y.·Zhang, W.·Thaxton, C.·Jin, Y.·Yatsula, B.·Bai, H.·Davis, S.·Exsted, T.·Dardik, A.·Guzman, R. J.·Cai, Y.
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Abstract

Objective- Surgically created upper extremity arteriovenous fistulae (AVF) are the preferred vascular access for patients requiring dialysis. It is estimated, however, that 50% of AVF fail within one year due to aggressive neointimal hyperplasia, which significantly increases morbidity and mortality. Matrix metalloproteinase-3 (MMP-3), also known as stromelysin-1, is a member of the metalloproteinase family that plays a critical role in the pathogenesis of many human disorders by degrading extracellular matrix and regulating molecular signaling pathways. The role of MMP- 3 in AVF neointimal failure has not been explored. Approach and Results- We observed that MMP-3 was induced in a time-dependent fashion by fetal bovine serum (FBS) and the growth factor PDGF-BB in cultured venous SMC. MMP-3 was also highly expressed in the neointimal SMCs of the outflow veins and the juxta-anastomotic area in an AVF mouse model, as well as in human AVF specimens. Knockdown of MMP-3 significantly suppressed venous SMC proliferation, whereas overexpression of MMP-3 facilitated cell growth in vitro. Importantly, deficiency of global and SMC-specific MMP-3 significantly reduced neointimal hyperplasia and improved patency after AVF creation. Mechanistic studies showed that MMP-3-mediated SMC proliferation and AVF neointimal hyperplasia were regulated via the FAK-AKT signaling pathway. Conclusions- These data suggest that MMP-3 is a key mediator of AVF neointimal failure. Targeting local MMP-3 activity may be a novel therapeutic strategy to prevent AVF neointimal failure and improve outcomes in patients requiring hemodialysis.

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Xie, Y., Zhang, W., Thaxton, C., Jin, Y., Yatsula, B., Bai, H., Davis, S., Exsted, T., Dardik, A., Guzman, R. J., Cai, Y.. 2025-08-30. Matrix metalloproteinase-3 promotes arteriovenous fistula failure by regulating FAK-AKT signaling. https://doi.org/10.1101/2025.08.27.672378

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