Sun Ye, Liu Chi-Hsiu, Wang Zhongxiao, Meng Steven S, Burnim Samuel B, SanGiovanni John Paul, Kamenecka Theodore M, Solt Laura A, Chen Jing
Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, Massachusetts, USA.
Section of Nutritional Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA.
FASEB J. 2017 Oct;31(10):4492-4502. doi: 10.1096/fj.201700172R. Epub 2017 Jun 23.
Pathological proliferation of retinal blood vessels commonly causes vision impairment in proliferative retinopathies, including retinopathy of prematurity. Dysregulated crosstalk between the vasculature and retinal neurons is increasingly recognized as a major factor contributing to the pathogenesis of vascular diseases. Class 3 semaphorins (SEMA3s), a group of neuron-secreted axonal and vascular guidance factors, suppress pathological vascular growth in retinopathy. However, the upstream transcriptional regulators that mediate the function of SEMA3s in vascular growth are poorly understood. Here we showed that retinoic acid receptor-related orphan receptor α (RORα), a nuclear receptor and transcription factor, is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in a mouse model of oxygen-induced proliferative retinopathy. We found that genetic deficiency of RORα substantially induced expression in retinopathy. Both RORα and SEMA3E were expressed in retinal ganglion cells. RORα directly bound to a specific ROR response element on the promoter of and negatively regulated promoter-driven luciferase expression. Suppression of using adeno-associated virus 2 carrying short hairpin RNA targeting promoted disoriented pathological neovascularization and partially abolished the inhibitory vascular effects of RORα deficiency in retinopathy. Our findings suggest that RORα is a novel transcriptional regulator of SEMA3E-mediated neurovascular coupling in pathological retinal angiogenesis.-Sun, Y., Liu, C.-H., Wang, Z., Meng, S. S., Burnim, S. B., SanGiovanni, J. P., Kamenecka, T. M., Solt, L. A., Chen, J. RORα modulates semaphorin 3E transcription and neurovascular interaction in pathological retinal angiogenesis.
视网膜血管的病理性增殖通常会导致增殖性视网膜病变（包括早产儿视网膜病变）的视力损害。血管系统与视网膜神经元之间失调的相互作用日益被认为是导致血管疾病发病机制的主要因素。3类信号素（SEMA3s）是一组由神经元分泌的轴突和血管导向因子，可抑制视网膜病变中病理性血管的生长。然而，介导SEMA3s在血管生长中功能的上游转录调节因子尚不清楚。在这里，我们表明视黄酸受体相关孤儿受体α（RORα）是一种核受体和转录因子，在氧诱导的增殖性视网膜病变小鼠模型中，它是SEMA3E介导的神经血管耦合的新型转录调节因子。我们发现RORα基因缺陷在视网膜病变中显著诱导了[具体基因名称未给出]的表达。RORα和SEMA3E均在视网膜神经节细胞中表达。RORα直接与[具体基因名称未给出]启动子上的特定ROR反应元件结合，并负调控[具体基因名称未给出]启动子驱动的荧光素酶表达。使用携带靶向[具体基因名称未给出]的短发夹RNA的腺相关病毒2抑制[具体基因名称未给出]可促进紊乱的病理性新生血管形成，并部分消除RORα缺陷在视网膜病变中的血管抑制作用。我们的研究结果表明，RORα是病理性视网膜血管生成中SEMA3E介导的神经血管耦合的新型转录调节因子。-孙，Y.，刘，C.-H.，王，Z.，孟，S.S.，伯宁姆，S.B.，桑乔瓦尼，J.P.，卡梅内卡，T.M.，索尔特，L.A.，陈，J.RORα调节病理性视网膜血管生成中的信号素3E转录和神经血管相互作用。
