Geenen Irma L, Kolk Felix F, Molin Daniel G, Wagenaar Allard, Compeer Mathijs G, Tordoir Jan H, Schurink Geert W, De Mey Jo G, Post Mark J
Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of General Surgery, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
PLoS One. 2016 Jan 4;11(1):e0146212. doi: 10.1371/journal.pone.0146212. eCollection 2016.
Autologous arteriovenous (AV) fistulas are the first choice for vascular access but have a high risk of non-maturation due to insufficient vessel adaptation, a process dependent on nitric oxide (NO)-signaling. Chronic kidney disease (CKD) is associated with oxidative stress that can disturb NO-signaling. Here, we evaluated the influence of CKD on AV fistula maturation and NO-signaling.
CKD was established in rats by a 5/6th nephrectomy and after 6 weeks, an AV fistula was created between the carotid artery and jugular vein, which was followed up at 3 weeks with ultrasound and flow assessments. Vessel wall histology was assessed afterwards and vasoreactivity of carotid arteries was studied in a wire myograph. The soluble guanylate cyclase (sGC) activator BAY 60-2770 was administered daily to CKD animals for 3 weeks to enhance fistula maturation.
CKD animals showed lower flow rates, smaller fistula diameters and increased oxidative stress levels in the vessel wall. Endothelium-dependent relaxation was comparable but vasorelaxation after sodium nitroprusside was diminished in CKD vessels, indicating NO resistance of the NO-receptor sGC. This was confirmed by stimulation with BAY 60-2770 resulting in increased vasorelaxation in CKD vessels. Oral administration of BAY 60-2770 to CKD animals induced larger fistula diameters, however; flow was not significantly different from vehicle-treated CKD animals.
CKD induces oxidative stress resulting in NO resistance that can hamper AV fistula maturation. sGC activators like BAY 60-2770 could offer therapeutic potential to increase AV fistula maturation.
自体动静脉内瘘是血管通路的首选，但由于血管适应性不足，存在较高的未成熟风险，这一过程依赖于一氧化氮（NO）信号传导。慢性肾脏病（CKD）与氧化应激相关，氧化应激会干扰NO信号传导。在此，我们评估了CKD对动静脉内瘘成熟及NO信号传导的影响。
通过5/6肾切除术在大鼠中建立CKD模型，6周后在颈动脉和颈静脉之间建立动静脉内瘘，3周后通过超声和血流评估进行随访。随后评估血管壁组织学，并在血管张力测定仪中研究颈动脉的血管反应性。每天给CKD动物施用可溶性鸟苷酸环化酶（sGC）激活剂BAY 60 - 2770，持续3周，以促进内瘘成熟。
CKD动物的血流量较低，内瘘直径较小，血管壁氧化应激水平升高。内皮依赖性舒张功能相当，但CKD血管中硝普钠后的血管舒张功能减弱，表明NO受体sGC对NO有抵抗性。用BAY 60 - 2770刺激证实了这一点，导致CKD血管中的血管舒张增加。然而，给CKD动物口服BAY 60 - 2770可诱导更大的内瘘直径；血流量与接受载体处理的CKD动物无显著差异。
CKD诱导氧化应激，导致NO抵抗，从而阻碍动静脉内瘘成熟。像BAY 60 - 2770这样的sGC激活剂可能具有促进动静脉内瘘成熟的治疗潜力。
