Functions for platelet factor 4 (PF4/CXCL4) and its receptors in fibroblast-myofibroblast transition and fibrotic failure of arteriovenous fistulas (AVFs).

Autor: Xiao Y; Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA., Martinez L; DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA., Zigmond Z; DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA., Woltmann D; Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA., Singer DV; Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA., Singer HA; Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA., Vazquez-Padron RI; DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA., Salman LH; Department of Molecular & Cellular Physiology, Albany Medical College, Albany, NY, USA.; Division of Nephrology & Hypertension, Albany Medical College, Albany, NY, USA.
Jazyk: angličtina
Zdroj: The journal of vascular access [J Vasc Access] 2024 Nov; Vol. 25 (6), pp. 1911-1924. Date of Electronic Publication: 2023 Aug 17.
DOI: 10.1177/11297298231192386
Abstrakt: Background: Over 60% of End Stage Renal Disease (ESRD) patients are relying on hemodialysis (HD) to survive, and the arteriovenous fistula (AVF) is the preferred vascular access method for HD. However approximately half of all newly created AVF fail to mature and cannot be used without a salvage procedure. We have recently demonstrated an association between AVF maturation failure and post-operative fibrosis, while our RNA-seq study also revealed that veins that ultimately failed during AVF maturation had elevated levels of platelet factor 4 (PF4/CXCL4). However, a link between these two findings was yet to be established.
Methods: In this study, we investigated potential mechanisms between PF4 levels and fibrotic remodeling in veins. We compared the local expression of PF4 and fibrosis marker integrin β 6 (ITGB6) in veins that successfully underwent maturation with that in veins that ultimately failed to mature. We also measured the changes of expression level of α-smooth muscle actin (αSMA/ ACTA2 ) and collagen (Col1/ COL1A1 ) in venous fibroblasts upon various treatments, such as PF4 pharmacological treatment, alteration of PF4 expression, and blocking of PF4 receptors.
Results: We found that PF4 is expressed in veins and co-localizes with αSMA. In venous fibroblasts, PF4 stimulates expression of αSMA and Col1 via different pathways. The former requires integrins α v β 5 and α 5 β 1 , while chemokine receptor CXCR3 is needed for the latter. Interestingly, we also discovered that the expression of PF4 is associated with that of ITGB6, the β subunit of integrin α v β 6 . This integrin is critical for the activation of the major fibrosis factor TGFβ, and overexpression of PF4 promotes activation of the TGFβ pathway.
Conclusions: These results indicate that upregulation of PF4 may cause venous fibrosis both directly by stimulating fibroblast differentiation and expression of extracellular matrix (ECM) molecules and indirectly by facilitating the activation of the TGFβ pathway.
Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Databáze: MEDLINE
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