Department of Ophthalmology and.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
JCI Insight. 2017 Sep 21;2(18). doi: 10.1172/jci.insight.95530.
Clinical trials in patients with macular edema due to diabetic retinopathy or retinal vein occlusion (RVO) have shown that suppression of VEGF not only improves macular edema, but also reopens closed retinal vessels, prevents progression of vessel closure, and improves retinopathy. In this study, we show the molecular basis for those clinical observations. Increased retinal levels of VEGF in mice cause plugging of retinal vessels with leukocytes, vessel closure, and hypoxia. Suppression of VEGF reduces leukocyte plugging, causing reperfusion of closed vessels. Activation of VEGFR1 contributes to leukocyte recruitment, because it is significantly reduced by an anti-VEGFR1-neutralizing antibody. High VEGF increases transcriptional activity of NF-κB and expression of NF-κB target genes, particularly Vcam1. Injection of an anti-VCAM-1-neutralizing antibody reduces VEGF-induced leukocyte plugging. These data explain the broad range of benefits obtained by VEGF suppression in patients with ischemic retinopathies, provide an important insight into the pathogenesis of RVO and diabetic retinopathy, and suggest that sustained suppression of VEGF early in the course of these diseases may prevent vessel closure, worsening ischemia, and disease progression. This study also identifies VEGFR1 and VCAM-1 as molecular targets whose suppression could supplement VEGF neutralization for treatment of RVO and diabetic retinopathy.
患有糖尿病性视网膜病变或视网膜静脉阻塞（RVO）引起的黄斑水肿的患者的临床试验表明，VEGF 的抑制不仅可以改善黄斑水肿，还可以重新开放封闭的视网膜血管，防止血管闭塞进展，并改善视网膜病变。在这项研究中，我们展示了这些临床观察的分子基础。在小鼠中，视网膜中 VEGF 的增加会导致白细胞堵塞视网膜血管、血管闭塞和缺氧。VEGF 的抑制减少白细胞堵塞，导致封闭血管再灌注。VEGFR1 的激活有助于白细胞募集，因为它会被抗 VEGFR1 中和抗体显著减少。高 VEGF 增加 NF-κB 的转录活性和 NF-κB 靶基因的表达，特别是 VCAM1。注射抗 VCAM-1 中和抗体可减少 VEGF 诱导的白细胞堵塞。这些数据解释了 VEGF 抑制在缺血性视网膜病变患者中获得的广泛益处，为 RVO 和糖尿病性视网膜病变的发病机制提供了重要的见解，并表明在这些疾病的早期持续抑制 VEGF 可能防止血管闭塞、加重缺血和疾病进展。这项研究还确定了 VEGFR1 和 VCAM-1 作为分子靶点，其抑制作用可能补充 VEGF 中和作用，用于治疗 RVO 和糖尿病性视网膜病变。
