Increasing nitric oxide bioavailability fails to improve collateral vessel formation in humanized sickle cell mice.
Increasing nitric oxide bioavailability fails to improve collateral vessel formation in humanized sickle cell mice.
复制标题
DOI：
10.1038/s41374-022-00780-0
复制
发表时间：
2022-08
影响因子：
5
通讯作者：
Taylor, W. Robert
中科院分区：
文献类型：
--
作者：
Lewis, Caitlin, V;Sellak, Hassan;Hansen, Laura;Joseph, Giji;Hurtado, Julian;Archer, David R.;Jun, Ho-Wook;Brown, Lou Ann;Taylor, W. Robert
镰状细胞病（SCD）与反复发作的血管功能不全相关，导致器官功能障碍。血管损伤后的血运重建缺陷在SCD患者和动物模型中是明显的。我们的目的是阐明是否提高一氧化氮在SCD小鼠的生物利用度改善血管功能不全模型的结果。Townes AA（野生型）和SS（镰状细胞）小鼠用L-精氨酸（在饮用水中5%）、L-NAME（N（ω）-硝基-L-精氨酸甲酯;在饮用水中lg/L）或NO生成水凝胶（PA-YK-NO）处理，然后通过股动脉结扎和切除进行后肢缺血。通过激光多普勒灌注成像监测灌注恢复超过28天。与之前的发现一致，SS小鼠的灌注受损（AA中63±4%的非缺血性肢体灌注vs SS中33±3%;第28天; P<0.001; n=5-7），并与坏死增加相关。L-精氨酸治疗对灌注恢复或坏死没有显著影响（n=5-7）。PA-YK-NO处理导致恶化的灌注恢复（19±3对赋形剂处理的小鼠中的32±3;第7天; P<0.05; n=4-5），增加的坏死评分（P<0.05，n=4-5）和后肢过氧亚硝酸盐增加46%（P=0.055，n=4-5）。有趣的是，L-NAME使SS小鼠的结果恶化，缺血后体内凝集素染色减少（未治疗小鼠的7±2%面积对治疗小鼠的4±2%面积，P<0.05，n=5）。我们的研究结果表明，L-精氨酸和直接NO交付都未能改善缺血后的新血管形成在SCD。在SCD的炎症、氧化环境中添加NO可能导致进一步的氧化应激并限制恢复。
Sickle cell disease (SCD) is associated with repeated bouts of vascular insufficiency leading to organ dysfunction. Deficits in revascularization following vascular injury are evident in SCD patients and animal models. We aimed to elucidate whether enhancing nitric oxide bioavailability in SCD mice improves outcomes in a model of vascular insufficiency. Townes AA (wild type) and SS (sickle cell) mice were treated with either L-Arginine (5% in drinking water), L-NAME (N(ω)-nitro-L-arginine methyl ester; 1 g/L in drinking water) or NO-generating hydrogel (PA-YK-NO), then subjected to hindlimb ischemia via femoral artery ligation and excision. Perfusion recovery was monitored over 28 days via LASER Doppler perfusion imaging. Consistent with previous findings, perfusion was impaired in SS mice (63±4% of non-ischemic limb perfusion in AA vs 33±3% in SS; day 28; P<0.001; n=5–7) and associated with increased necrosis. L-Arginine treatment had no significant effect on perfusion recovery or necrosis (n=5–7). PA-YK-NO treatment led to worsened perfusion recovery (19±3 vs 32±3 in vehicle-treated mice; day 7; P<0.05; n=4–5), increased necrosis score (P<0.05, n=4–5) and a 46% increase in hindlimb peroxynitrite (P=0.055, n=4–5). Interestingly, L-NAME worsened outcomes in SS mice with decreased in vivo lectin staining following ischemia (7±2% area in untreated vs 4±2% in treated mice, P<0.05, n=5). Our findings demonstrate that L-arginine and direct NO delivery both fail to improve postischemic neovascularization in SCD. Addition of NO to the inflammatory, oxidative environment in SCD may result in further oxidative stress and limit recovery.
登录
查看更多内容
影响因子：
3.4
作者：
Kauv, Paul;Gaudre, Noemie;Bartolucci, Pablo
通讯作者：
Bartolucci, Pablo
影响因子：
3.1
作者：
Gkaliagkousi, Eugenia;Ferro, Albert
通讯作者：
Ferro, Albert
影响因子：
--
作者：
Eleuterio, Renata M N;Nascimento, Francisco O;Lemes, Romelia P G
通讯作者：
Lemes, Romelia P G
DOI：
10.1016/j.pathophys.2015.05.001
发表时间：
2015-09-01
期刊：
Pathophysiology : the official journal of the International Society for Pathophysiology
影响因子：
--
作者：
Kehinde, M O;Ogungbemi, S I;Jaja, S I
通讯作者：
Jaja, S I
影响因子：
20.3
作者：
Hsu, Lewis L.;Champion, Hunter C.;Gladwin, Mark T.
通讯作者：
Gladwin, Mark T.