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Function of TGFβ (Transforming Growth Factor-β) Receptor in the Vein Is Not in Vain

Originally publishedhttps://doi.org/10.1161/ATVBAHA.122.317861Arteriosclerosis, Thrombosis, and Vascular Biology. 2022;42:884–885

See accompanying article on page 868

Hemodialysis is a critical procedure in patients with renal failure. An arteriovenous fistula (AVF) is created to gain vascular access that can be repeatedly used for effective and efficient hemodialysis. Subsequent to AVF formation, the vein undergoes maturation and structural remodeling that accommodates sufficient blood flow during dialysis and repetitive access. Maturation failure of the AVF, or excess remodeling and stenosis of the venous wall, are significant causes of morbidity and hospitalization in dialysis patients. This prompts the need for understanding the cellular and molecular mechanism underlying the AVF maturation process.

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Taniguchi et al1 report that targeting the TGFBR (TGFβ [transforming growth factor β] receptor) can improve AVF patency. This study disrupted the TGFβ pathway by a pharmacological agent, and by genetic cell specific deletion of TGFβ receptor in smooth muscle cells (SMCs, Tgfbr2flx/flx/Myh11-CreERT2) or endothelial cells (ECs, Tgfbr1/2flx/flx/Cdh5-CreERT2; Figure). Pharmacological inhibition of TGFBR improved overall remodeling of the vein and improved patency of the AVF as assessed by ultrasound, although the long-term functional efficacy of the fistula with repeated vascular access was not assessed. This study further identifies the ECs as a more effective target for TGFBR inhibition compared with SMCs since deletion of TGFBR in ECs suppressed SMC proliferation, collagen deposition, medial wall thickness and improved outward remodeling, whereas in SMCs, TGFBR2 deletion only reduced collagen synthesis without decreasing SMC proliferation nor wall thickness. AVF stenosis has been linked to neointimal hyperplasia, characterized by excessive accumulation of SMCs and extracellular matrix, and inadequate outward remodeling of the venous wall.2 The findings by Taniguchi et al also suggest an important paracrine effects of TGFβ pathway such that ablation of TGFBR in ECs can regulate proliferation and function of SMCs. The underlying mechanism of this paracrine function of TGFβ receptor requires further investigation.

Figure.

Figure. Pharmacological and cell-specific inhibition of TGFβ (transforming growth factor β) receptors, in smooth muscle cells (SMCs) or endothelial cells (ECs) in remodeling of venous wall in arteriovenous fistula (AVF). The dotted arrows show where there was an increase or decrease but it did not reach statistical significance.

TGFβ is a well-studied anti-inflammatory cytokine best known for its profibrotic function, as well as its involvement in a number of vascular pathologies such as aortic aneurysm,3,4 atherosclerosis,5 and vein graft remodeling.6 TGFβ expression is increased in both mouse and human AVF.7–9 Bioavailability of TGFβ (ligand) involves a number of steps including synthesis (eg, by fibroblasts or SMCs), release into the extracellular space noncovalently bound to LAP (latency associated proprotein) forming the small latent complex, which is sequestered in the extracellular matrix bound to LTBP (latent TGFβ-binding protein) forming the large latent complex. Activation of the latent TGFβ requires proteolytic cleavage of the LTBP, usually by a MMP (matrix metalloproteinase), release of the small latent complex, and subsequently the release of the TGFβ dimer that binds to TGFBR2 triggering its dimerization with TGFBR1 and activation of the downstream canonical Smad 2/3 pathway, or the noncanonical MAPK (mitogen-activated protein kinase) pathway through activation of TAK1 (TGFβ-activated kinase 1).10 In the study by Taniguchi et al, authors targeted the TGFβ receptor rather than its ligand (TGFβ) which can be a more direct approach in disrupting the TGFβ-mediated pathways. However, it is important to note that other ligands, including BMPs (morphogenic proteins) and activin, 2 members of the TGFβ superfamily, can also bind to and activate TGFB1/2. As such, the impact of targeting TGFBR may not be limited to inhibition of TGFβ actions and could imply involvement of other molecules in addition to TGFβ.

Taniguchi et al1 identified the ECs as the key cell type in regulating venous remodeling in the AVF. Using a similar mouse AVF model, an earlier study reported that AVF formation resulted in a significant increase in the blood pressure in the vein due to its exposure to the aortic flow.11 Exposure of mouse ECs to a laminar shear stress equivalent to that in the arterial flow increased activation of the noncanonical TGFβ signaling pathway, that is, phosphorylation of TAK1 and MAPK.12 This study also supports the involvement of the TGFβ pathway in AVF maturation although through the noncanonical pathway downstream of TGFβ receptors rather than the canonical Smad2/3 pathway as reported by Taniguchi et al.

In summary, the study by Taniguchi et al provides evidence on how disruption of the TGFBR-related signaling pathway in ECs can positively impact venous remodeling in the AVF. Therefore, targeted drug delivery to inhibit TGFBR in ECs at the AVF site could be a viable treatment option for dialysis patients. However, since AVF is created in patients with renal failure who often suffer from uremia that itself can cause vascular complications such as calcification, the beneficial impact of TGFBR inhibition in AVF stability should be confirmed in the presence of comorbidities such as uremia.

Article Information

Disclosures None.

Footnotes

For Sources of Funding and Disclosures, see page 885.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

Correspondence to: Zamaneh Kassiri, MSc, PhD, Professor, Department of Physiology, University of Alberta, Edmonton, AB, Canada, T6G 2S2. Email

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