Wu Yongdong, Lee Tae Hoon, Cheng Owen H, Peden Eric K, Li Qingtian, Wang Jun, Huang Fengzhang, Melancon Marites P, Sheikh-Hamad David, Wang Tao, Truong Luan, Mitch William E, Liang Ming, Cheng Jizhong
Section of Nephrology, Department of Medicine, Selzman Institute for Kidney Health, Baylor College of Medicine, Houston, Texas.
Department of Nephrology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.
J Am Soc Nephrol. 2025 May 1;36(5):845-858. doi: 10.1681/ASN.0000000605. Epub 2025 Jan 30.
Atrophied muscle–derived myostatin stimulated mesenchymal stem cell differentiation and adverse arteriovenous (AV) fistula remodeling through yes-associated protein 1 (YAP1) activation. Treatment with myostatin peptibody inhibited muscle wasting and blocked mesenchymal stem cell activation and AV fistula fibrosis. A light-sensitive drug-release strategy was engineered for the periadventitial delivery of verteporfin to improve AV fistula patency.
Arteriovenous (AV) fistulas are the preferred access for dialysis but have a high incidence of failure. The aim of this study was to understand the crosstalk between skeletal muscle catabolism and AV fistula maturation failure.
Skeletal muscle metabolism and AV fistula maturation were evaluated in mice with CKD. The roles of myostatin and yes-associated protein 1 (YAP1) in regulating the transdifferentiation of adventitial mesenchymal stem cells (MSCs) and intima hyperplasia in AV fistula were investigated. Nanoparticles carrying a YAP1 inhibitor, verteporfin, with light irradiation–controlled release were synthesized and applied to AV fistula.
Increased trichrome signals and stenosis were observed in AV fistulas from mice treated with myostatin and from mice with CKD. By contrast, blocking myostatin function with an anti-myostatin peptibody not only improved body weight and muscle size in CKD mice but also decreased neointima formation in AV fistulas. In cultured MSCs, myostatin induced YAP1 expression, promoting the differentiation of MSCs into myofibroblasts and inducing extracellular matrix deposition. Red light irradiation–controlled release of verteporfin from nanoparticles blocked YAP1 activation and alleviated myostatin-induced MSC activation. Periadventitial application and red light irradiation of nanoparticles carrying verteporfin significantly suppressed stiffening and neointima formation in AV fistula.
CKD induced muscle wasting, leading to increased production of myostatin, which stimulated MSC activation and vascular fibrosis linked to AV fistula stenosis. YAP1 signaling was activated in these processes. Red light irradiation–controlled release of verteporfin offered a feasible approach for local vascular drug intervention to improve AV fistula maturation.
萎缩肌肉来源的肌肉生长抑制素通过激活Yes相关蛋白1（YAP1）刺激间充质干细胞分化和动静脉（AV）内瘘不良重塑。肌肉生长抑制素肽抗体治疗可抑制肌肉萎缩，并阻断间充质干细胞激活和AV内瘘纤维化。设计了一种光敏感药物释放策略，用于在血管外膜周围递送维替泊芬以改善AV内瘘通畅性。
动静脉（AV）内瘘是透析的首选通路，但失败率很高。本研究的目的是了解骨骼肌分解代谢与AV内瘘成熟失败之间的相互作用。
在慢性肾脏病（CKD）小鼠中评估骨骼肌代谢和AV内瘘成熟情况。研究了肌肉生长抑制素和Yes相关蛋白1（YAP1）在调节AV内瘘外膜间充质干细胞（MSC）转分化和内膜增生中的作用。合成了携带YAP1抑制剂维替泊芬且具有光照射控制释放功能的纳米颗粒，并将其应用于AV内瘘。
在用肌肉生长抑制素处理的小鼠和CKD小鼠的AV内瘘中观察到三色染色信号增加和狭窄。相比之下，用抗肌肉生长抑制素肽抗体阻断肌肉生长抑制素功能不仅改善了CKD小鼠的体重和肌肉大小，还减少了AV内瘘中的新生内膜形成。在培养的MSC中，肌肉生长抑制素诱导YAP1表达，促进MSC分化为肌成纤维细胞并诱导细胞外基质沉积。纳米颗粒中维替泊芬的红光照射控制释放阻断了YAP1激活，并减轻了肌肉生长抑制素诱导的MSC激活。携带维替泊芬的纳米颗粒的血管外膜周围应用和红光照射显著抑制了AV内瘘的硬化和新生内膜形成。
CKD导致肌肉萎缩，导致肌肉生长抑制素产生增加，后者刺激MSC激活和与AV内瘘狭窄相关的血管纤维化。YAP1信号在这些过程中被激活。维替泊芬的红光照射控制释放为局部血管药物干预以改善AV内瘘成熟提供了一种可行的方法。
