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. 2023;7(2):129-140.
doi: 10.26502/fccm.92920318. Epub 2023 Apr 20.

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation

Nathaniel DeMarco  1 , Vikrant Rai  1 , Daniel R Wilson  1 , Devendra K Agrawal  1
Affiliations

Oncostatin M, Serpins, and Oxidative Stress in Extracellular Matrix Remodeling and Arteriovenous Fistula Maturation

Nathaniel DeMarco et al. Cardiol Cardiovasc Med. 2023.

Abstract

End-stage renal disease is a crippling diagnosis that generally requires dialysis to prolong life. To facilitate filtration of patient's blood in dialysis, surgical formation of an arteriovenous fistula (AVF) is commonly performed. Maturation of the AVF is required to allow for successful dialysis. However, AVFs commonly fail to mature, leading to the fistula closure, the necessity for another fistula site, and markedly increased morbidity and mortality. The current literature concerning molecular mechanisms associated with AVF maturation failure supports the role of inflammatory mediators involving immune cells and inflammatory cytokines. However, the role of oncostatin M (OSM), an inflammatory cytokine, and its downstream targets are not well investigated. Through inflammation, oxidative stress, and hypoxic conditions, the vascular tissue surrounding the AVF undergoes fibrosis, stenosis, and wall thickening, leading to complete occlusion and nonfunctional. In this report, first we critically review the existing literature on the role of OSM in the most common causes of early AVF failure - vascular inflammation, thrombosis, and stenosis. We next consider the potential of using OSM as a therapeutic target, and finally discuss therapeutic agents targeting inflammatory mediators involved in OSM signaling to potentiate successful maturation of the AVF.

Keywords: Arterio-Venous Fistula; Hypoxia; Inflammation; Oncostatin M; Oxidative Stress; Stenosis; Thrombosis.

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Figures

Figure 1:
Figure 1:
Oncostatin-M (OSM) secretion, downstream signaling, and regulation of molecular functions. Vascular tissue manipulation through stenting or arteriovenous fistula (AVF) creation leads to endothelial injury and subsequent immune cell recruitment including monocytes, macrophages, and neutrophils. The recruited immune cells secrete OSM which on binding with OSM-receptor (OSMR) leads to activation of downstream signaling that involve signal transducers and activator of transcription (STAT)3, phosphatidylinositol 3-kinases (PI3K), and protein kinase B (PKB/Akt). This regulates various molecular and cellular events including angiogenesis, extracellular matrix (ECM) remodeling, cell proliferation, migration, change in gene expression, and inflammation. Interleukin 6 receptor (IL6R), vascular endothelial growth factor (VEGF), and alpha-smooth muscle actin (α-SMA).
Figure 2:
Figure 2:
Schematics of possible targets in OSM-HIF1α-PAI-1 axis to enhance vascular remodeling and AVF maturation. Targeting circulating OSM in chronic inflammation may attenuate downstream signaling cascade and may enhance favorable vascular remodeling. Among downstream signals, targeting STAT3, oxidative stress, and PAI-1 may modulate cascade toward favorable ECM and vascular remodeling via inhibition of plasmin formation and overexpression of MMPs. Oncostatin-M (OSM), Oncostatin M receptor (OSMR), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), hypoxia-inducible factor-1-alpha (HIF-1α), extra cellular matrix (ECM), vascular smooth muscle cells (VSMCs), matrix metalloproteinases (MMPs).
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