Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.
Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.
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DOI：
10.1073/pnas.1423765112
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发表时间：
2015-06-09
影响因子：
11.1
通讯作者：
Sodhi A
中科院分区：
文献类型：
--
作者：
Babapoor-Farrokhran S;Jee K;Puchner B;Hassan SJ;Xin X;Rodrigues M;Kashiwabuchi F;Ma T;Hu K;Deshpande M;Daoud Y;Solomon S;Wenick A;Lutty GA;Semenza GL;Montaner S;Sodhi A
在增殖性糖尿病视网膜病变(PDR)中，视网膜缺血导致促进新生血管的血管生成因子的表达增加，这是糖尿病眼病最严重的后遗症。尽管针对血管生成介质血管内皮生长因子的治疗在治疗糖尿病黄斑水肿方面取得了显著的成功，但这一方法并不足以阻止视网膜新生血管的发展，提示额外的血管生成因子(S)参与了PDR的发病机制。我们在这里证明了血管生成素样4是一种强有力的血管生成介质，在PDR患者的眼睛中表达显著增加。我们的研究为眼部新生血管疾病的治疗确定了一个新的治疗靶点，并可能对其他依赖病理性血管生成的疾病的治疗具有广泛的意义。糖尿病眼病是发达国家劳动年龄人口严重视力丧失的最常见原因，增殖性糖尿病视网膜病变(PDR)是其最威胁视力的后遗症。在PDR中，视网膜缺血导致促进新生血管形成的血管生成因子上调。针对血管内皮生长因子的治疗延缓了部分(但不是全部)糖尿病患者的新生血管的发展，暗示了额外的因素(S)参与了糖尿病视网膜病变的发病机制。在这里，我们证明了PDR患者房水的血管生成潜能与血管内皮生长因子浓度无关，这为评估其他血管生成因子(S)在PDR发生中的作用提供了机会。我们发现血管生成素样蛋白4(Angiopoietin-like 4，ANGPTL4)是一种强有力的血管生成因子，在体外缺氧的视网膜Müler细胞和体内的缺血视网膜中表达上调。ANGPTL4在PDR患者房水和玻璃体中的表达增加，与VEGF水平无关，与糖尿病眼疾病的存在相关，并定位于视网膜新生血管区域。抑制ANGPTL4的表达降低了缺氧Müller细胞的血管生成能力；这种作用与抑制VEGF的表达是相加的。一种ANGPTL4中和抗体抑制了PDR患者房水的血管生成效应，包括来自低水平血管内皮生长因子或接受抗血管内皮生长因子治疗的患者的样本。总之，我们的研究结果表明，靶向ANGPTL4和VEGF对于有效治疗或预防PDR可能是必要的，并为评估房水中ANGPTL4作为生物标记物的研究提供了基础，以帮助指导糖尿病眼病的个体化治疗。
In proliferative diabetic retinopathy (PDR), the most vision-threatening sequela of diabetic eye disease, retinal ischemia leads to increased expression of angiogenic factors that promote neovascularization. Although therapies targeting the potent angiogenic mediator vascular endothelial growth factor have been remarkably successful for the treatment of diabetic macular edema, this approach has not proven sufficient to prevent the development of retinal neovascularization, implicating additional angiogenic factor(s) in PDR pathogenesis. We demonstrate here that angiopoietin-like 4 is a potent angiogenic mediator with markedly increased expression in the eyes of PDR patients. Our studies identify a novel therapeutic target for the treatment of ocular neovascular disease and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis. Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.
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影响因子：
7.7
作者：
McVicar CM;Hamilton R;Colhoun LM;Gardiner TA;Brines M;Cerami A;Stitt AW
通讯作者：
Stitt AW
影响因子：
4.2
作者：
Durham, Jennifer T.;Herman, Ira M.
通讯作者：
Herman, Ira M.
DOI：
10.1007/978-1-4614-3209-8_35
发表时间：
2014-01-01
期刊：
RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY
影响因子：
--
作者：
Kurihara, Toshihide;Westenskow, Peter D.;Friedlander, Martin
通讯作者：
Friedlander, Martin
影响因子：
4.4
作者：
McLeod DS;Grebe R;Bhutto I;Merges C;Baba T;Lutty GA
通讯作者：
Lutty GA
影响因子：
3.4
作者：
Ozaki, H;Hayashi, H;Oshima, K
通讯作者：
Oshima, K