Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada; Department of Biochemistry, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada.
Cell Metab. 2013 Oct 1;18(4):505-18. doi: 10.1016/j.cmet.2013.09.003.
The deterioration of the inner blood-retinal barrier and consequent macular edema is a cardinal manifestation of diabetic retinopathy (DR) and the clinical feature most closely associated with loss of sight. We provide evidence from both human and animal studies for the critical role of the classical neuronal guidance cue, semaphorin 3A, in instigating pathological vascular permeability in diabetic retinas via its cognate receptor neuropilin-1. We reveal that semaphorin 3A is induced in early hyperglycemic phases of diabetes within the neuronal retina and precipitates initial breakdown of endothelial barrier function. We demonstrate, by a series of orthogonal approaches, that neutralization of semaphorin 3A efficiently prevents diabetes-induced retinal vascular leakage in a stage of the disease when vascular endothelial growth factor neutralization is inefficient. These observations were corroborated in Tg(Cre-Esr1)/Nrp1(flox/flox) conditional knockout mice. Our findings identify a therapeutic target for macular edema and provide further evidence for neurovascular crosstalk in the pathogenesis of DR.
内血视网膜屏障的恶化以及随之而来的黄斑水肿是糖尿病性视网膜病变 (DR) 的主要表现，也是与视力丧失最密切相关的临床特征。我们提供了来自人类和动物研究的证据，证明经典的神经元导向线索——神经丝蛋白 3A 通过其同源受体神经纤毛蛋白 1，在糖尿病视网膜中引发病理性血管通透性方面起着关键作用。我们发现，神经丝蛋白 3A 在糖尿病的早期高血糖阶段在神经元视网膜中被诱导，引发内皮屏障功能的初始破坏。我们通过一系列正交方法证明，在血管内皮生长因子中和无效的疾病阶段，中和神经丝蛋白 3A 可有效地防止糖尿病引起的视网膜血管渗漏。在 Tg(Cre-Esr1)/Nrp1(flox/flox)条件性敲除小鼠中证实了这些观察结果。我们的发现为黄斑水肿提供了一个治疗靶点，并为 DR 发病机制中的神经血管相互作用提供了进一步的证据。
