From the Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA (D.-O.D., L.H., G.J., A.N.L., D.W., W.R.T.).
Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta, Emory University School of Medicine, GA (D.R.A.).
Arterioscler Thromb Vasc Biol. 2018 May;38(5):1125-1133. doi: 10.1161/ATVBAHA.118.310771. Epub 2018 Mar 15.
The adaptive response to vascular injury is the formation of functional collateral vessels to maintain organ integrity. Many of the clinical complications associated with sickle cell disease can be attributed to repeated bouts of vascular insufficiency, yet the detailed mechanisms of collateral vessel formation after injury are largely unknown in sickle cell disease. Here, we characterize postischemic neovascularization in sickle cell disease and the role of neutrophils in the production of reactive oxygen species.
We induced hindlimb ischemia by ligation of the femoral artery in Townes SS (sickle cell) mice compared with AA (wild type) mice. Perfusion recovery, ascertained using LASER (light amplification by stimulated emission of radiation) Doppler perfusion imaging, showed significant diminution in collateral vessel formation in SS mice after hindlimb ischemia (76±13% AA versus 34±10% in SS by day 28; <0.001; n=10 per group). The incidence of amputation (25% versus 5%) and foot necrosis (80% versus 15%) after hindlimb ischemia was significantly increased in the SS mice. Motor function recovery evaluation by the running wheel assay was also impaired in SS mice (36% versus 97% at 28 days post-hindlimb ischemia; <0.001). This phenotype was associated with persistent and excessive production of reactive oxygen species by neutrophils. Importantly, neutrophil depletion or treatment with the antioxidant N-acetylcysteine reduced oxidative stress and improved functional collateral formation in the SS mice.
Our data suggest dysfunctional collateral vessel formation in SS mice after vascular injury and provide a mechanistic basis for the multiple vascular complications of sickle cell disease.
血管损伤的适应性反应是形成功能性侧支血管以维持器官完整性。镰状细胞病相关的许多临床并发症可归因于反复发生的血管功能不全，但在镰状细胞病中，损伤后侧支血管形成的详细机制在很大程度上尚不清楚。在这里，我们描述了镰状细胞病中的缺血后新生血管形成和中性粒细胞在产生活性氧中的作用。
我们通过结扎股动脉在 Townes SS（镰状细胞）小鼠中诱导后肢缺血，并与 AA（野生型）小鼠进行比较。使用 LASER（受激辐射光放大）多普勒灌注成像来确定灌注恢复，结果显示 SS 小鼠在缺血后侧支血管形成明显减少（28 天时 AA 组为 76±13%，SS 组为 34±10%；<0.001；每组 n=10）。SS 小鼠的后肢缺血后截肢（25%对 5%）和足部坏死（80%对 15%）发生率显著增加。通过跑步轮试验评估运动功能恢复也在 SS 小鼠中受损（缺血后 28 天 36%对 97%；<0.001）。这种表型与中性粒细胞持续和过度产生活性氧有关。重要的是，中性粒细胞耗竭或用抗氧化剂 N-乙酰半胱氨酸治疗可减少 SS 小鼠的氧化应激并改善功能性侧支形成。
我们的数据表明 SS 小鼠在血管损伤后侧支血管形成功能障碍，并为镰状细胞病的多种血管并发症提供了机制基础。
