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Endothelial TGF-ß Signaling Regulates Endothelial-Mesenchymal Transition During Arteriovenous Fistula Remodeling in Mice With Chronic Kidney Disease.
Zhang, Weichang; Gonzalez, Luis; Li, Xin; Bai, Hualong; Li, Zhuo; Taniguchi, Ryosuke; Langford, John; Ohashi, Yuichi; Thaxton, Carly; Yukihiko, Aoyagi; Yatsula, Bogdan; Martin, Kathleen; Goodwin, Julie; Tellides, George; Long, Xiaochun; Shu, Chang; Dardik, Alan.
Afiliación
  • Zhang W; State Key Laboratory of Cardiovascular Diseases, Center of Vascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China (W.Z., C.S.).
  • Gonzalez L; Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China (W.Z., X. Li, C.S.).
  • Li X; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Bai H; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Li Z; Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China (W.Z., X. Li, C.S.).
  • Taniguchi R; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Langford J; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Ohashi Y; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Thaxton C; Division of Vascular Surgery, The University of Tokyo, Japan (R.T., Y.O.).
  • Yukihiko A; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Yatsula B; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Martin K; Division of Vascular Surgery, The University of Tokyo, Japan (R.T., Y.O.).
  • Goodwin J; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Tellides G; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Long X; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Shu C; Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT. (W.Z., L.G., H.B., Z.L., R.T., J.L., Y.O., C.T., A.Y., B.Y., K.M., J.G., G.T., A.D.).
  • Dardik A; Department of Medicine (Cardiovascular Medicine), Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT. (K.M.).
Arterioscler Thromb Vasc Biol ; 2024 Sep 19.
Article en En | MEDLINE | ID: mdl-39297205
ABSTRACT

BACKGROUND:

Arteriovenous fistulae (AVFs) are the preferred vascular access for hemodialysis in patients with end-stage kidney disease. Chronic kidney disease (CKD) is associated with endothelial injury, impaired AVF maturation, and reduced patency, as well as utilization. Because CKD is characterized by multiple pathophysiological processes that induce endothelial-to-mesenchymal transition (EndMT), we hypothesized that CKD promotes EndMT during venous remodeling and that disruption of endothelial TGF (transforming growth factor)-ß signaling inhibits EndMT to prevent AVF failure even in the end-stage kidney disease environment.

METHODS:

The mouse 5/6 nephrectomy and aortocaval fistula models were used. CKD was created via 5/6 nephrectomy, with controls of no (0/6) or partial (3/6) nephrectomy in C57BL/6J mice. AVFs were created in mice with knockdown of TGF-ßR1/R2 (TGF-ß receptors type 1/2) in either smooth muscle cells or endothelial cells. AVF diameters and patency were measured and confirmed by serial ultrasound examination. AVF, both murine and human, were examined using Western blot, histology, and immunofluorescence. Human and mouse endothelial cells were used for in vitro experiments.

RESULTS:

CKD accelerates TGF-ß activation and promotes EndMT that is associated with increased AVF wall thickness and reduced patency in mice. Inhibition of TGF-ß signaling in both endothelial cells and smooth muscle cells decreased smooth muscle cell proliferation in the AVF wall, attenuated EndMT, and was associated with reduced wall thickness, increased outward remodeling, and improved AVF patency. Human AVF also showed increased TGF-ß signaling and EndMT.

CONCLUSIONS:

CKD promotes EndMT and reduces AVF patency. Inhibition of TGF-ß signaling, especially disruption of endothelial cell-specific TGF-ß signaling, attenuates EndMT and improves AVF patency in mouse AVF. Inhibition of EndMT may be a therapeutic approach of translational significance to improve AVF patency in human patients with CKD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos