Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.
Delineating effects of angiopoietin-2 inhibition on vascular permeability and inflammation in models of retinal neovascularization and ischemia/reperfusion.
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DOI：
10.3389/fncel.2023.1192464
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发表时间：
2023
影响因子：
5.3
通讯作者：
Westenskow, Peter D.
中科院分区：
文献类型：
--
作者：
Canonica, Jeremie;Foxton, Richard;Garrido, Marina Garcia;Lin, Cheng-Mao;Uhles, Sabine;Shanmugam, Sumathi;Antonetti, David A.;Abcouwer, Steven F.;Westenskow, Peter D.
关键词：
临床试验表明，在新生血管性老年性黄斑变性和糖尿病黄斑水肿患者中，联合靶向血管生成素-2(Ang-2)和血管内皮生长因子(VEGF-A)的Faricimab可以控制解剖结果，并在两年内保持视力改善，具有很强的持久性。这些发现背后的机制(S)还不完全清楚，Ang-2抑制所起的具体作用还需要进一步研究。我们研究了单独和双重抑制Ang-2/VEGF-A对自发性脉络膜新生血管(CNV)和视网膜缺血/再灌注(I/R)损伤的JR5558小鼠病变血管的影响。在JR5558小鼠中，Ang-2、VEGF-A和Dual Ang-2/VEGF-A抑制1周后减少新生血管面积；仅Dual Ang-2/VEGF-A抑制减少新生血管渗漏。仅Ang-2和Dual Ang-2/VEGF-A抑制作用在5周后维持下降。双重Ang-2/VEGF-A抑制作用1周后可减少巨噬细胞/小胶质细胞在病灶周围的聚集。5周后，Ang-2和双重Ang-2/VEGF-A抑制均可减少病灶周围巨噬细胞/小胶质细胞的聚集。在视网膜I/R损伤模型中，双重抑制Ang-2/VEGF-A在预防视网膜血管渗漏和神经变性方面明显优于单独应用Ang-2或VEGF-A。这些数据强调了Ang-2在双重抑制Ang-2/VEGF-A中的作用，并表明双重抑制具有互补的抗炎和神经保护作用，提示法利昔单抗在临床试验中的持久性和有效性的机制。
Clinical trials demonstrated that co-targeting angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF-A) with faricimab controls anatomic outcomes and maintains vision improvements, with strong durability, through 2 years in patients with neovascular age-related macular degeneration and diabetic macular edema. The mechanism(s) underlying these findings is incompletely understood and the specific role that Ang-2 inhibition plays requires further investigation. We examined the effects of single and dual Ang-2/VEGF-A inhibition in diseased vasculatures of JR5558 mice with spontaneous choroidal neovascularization (CNV) and in mice with retinal ischemia/reperfusion (I/R) injuries. In JR5558 mice, Ang-2, VEGF-A, and dual Ang-2/VEGF-A inhibition reduced CNV area after 1 week; only dual Ang-2/VEGF-A inhibition decreased neovascular leakage. Only Ang-2 and dual Ang-2/VEGF-A inhibition maintained reductions after 5 weeks. Dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 1 week. Both Ang-2 and dual Ang-2/VEGF-A inhibition reduced macrophage/microglia accumulation around lesions after 5 weeks. In the retinal I/R injury model, dual Ang-2/VEGF-A inhibition was statistically significantly more effective than Ang-2 or VEGF-A inhibition alone in preventing retinal vascular leakage and neurodegeneration. These data highlight the role of Ang-2 in dual Ang-2/VEGF-A inhibition and indicate that dual inhibition has complementary anti-inflammatory and neuroprotective effects, suggesting a mechanism for the durability and efficacy of faricimab in clinical trials.
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DOI：
10.1038/s41433-020-0895-z
发表时间：
2020-11
期刊：
Eye (London, England)
影响因子：
--
作者：
Adamis AP;Brittain CJ;Dandekar A;Hopkins JJ
通讯作者：
Hopkins JJ
影响因子：
40.5
作者：
Antonetti, David A.;Silva, Paolo S.;Stitt, Alan W.
通讯作者：
Stitt, Alan W.
影响因子：
4.4
作者：
Nagai, Norihiro;von Leithner, Pete Lundh;Shima, David T.
通讯作者：
Shima, David T.
影响因子：
4.4
作者：
Abcouwer, Steven F.;Lin, Cheng-mao;Antonetti, David A.
通讯作者：
Antonetti, David A.
影响因子：
4.5
作者：
Chakravarthy, Usha;Bailey, Clare;Schwab, Dietmar
通讯作者：
Schwab, Dietmar