Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye.
Blockade of VEGFR1 and 2 suppresses pathological angiogenesis and vascular leakage in the eye.
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DOI：
10.1371/journal.pone.0021411
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Vinores SA
中科院分区：
文献类型：
--
作者：
Huang H;Shen J;Vinores SA
血管内皮生长因子受体1和血管内皮生长因子2信号转导通路在缺血性视网膜病变的并发症中起重要作用，包括早产儿视网膜病变(ROP)、老年性黄斑变性(AMD)和糖尿病视网膜病变(DR)。本研究评价了阻断VEGFR1和2对ROP模型中缺血性视网膜病变和AMD模型中脉络膜新生血管(CNV)的病理性血管生成和血管渗漏的影响。系统注射小鼠VEGFR1(MF1)和VEGFR2(DC101)中和抗体。激光光凝诱导新生血管形成，激光治疗14d后评估新生血管。视网膜NV是在氧诱导的缺血性视网膜病变(OIR)中产生的，并在p17进行评估。通过测量NV束来确定NV定量，通过测量从血管到视网膜的[~3H]-甘露醇渗漏量来定量血管渗漏。实时定量聚合酶链式反应检测基因表达。VEGFR1和VEGFR2在CNV发病过程中表达上调。MF1和DC101在50 mg/kg时对新生血管均有明显的抑制作用：DC101对CNV的抑制作用为73±5%(p<；0.0001)，对MF1的抑制作用为±6%(p = 0.0002)，且呈剂量依赖关系。MF1和DC101的联合应用增强了抑制效应，并导致视网膜小胶质细胞在CNV损伤处聚集。同样，Mf1和DC101在50 mg/kg时均能显著抑制OIR中的视网膜NV：DC101对视网膜NV的抑制率为54±8%(p = 0.013)，对MF1的抑制率为50±7%(p<；0.0002)。MF1比DC101更有效地抑制缺血诱导的视网膜/肺破裂：MF1使视网膜/肺渗漏比减少73±24%，p = 为0.001；DC101减少12±4%，p = 为0.003。MF1组视网膜/肾渗漏比减少52±28%，p = 为0.009；DC101组减少13±4%，p = 为0.001。我们的研究提供了进一步的证据，表明VEGFR1和2在这些眼病模型中都介导了病理性血管生成和血管渗漏，并提示这些受体酪氨酸激酶(RTK)的拮抗剂是潜在的治疗药物。
VEGFR1 and 2 signaling have both been increasingly shown to mediate complications of ischemic retinopathies, including retinopathy of prematurity (ROP), age-related macular degeneration (AMD), and diabetic retinopathy (DR). This study evaluates the effects of blocking VEGFR1 and 2 on pathological angiogenesis and vascular leakage in ischemic retinopathy in a model of ROP and in choroidal neovascularization (CNV) in a model of AMD. Neutralizing antibodies specific for mouse VEGFR1 (MF1) and VEGFR2 (DC101) were administrated systemically. CNV was induced by laser photocoagulation and assessed 14d after laser treatment. Retinal NV was generated in oxygen-induced ischemic retinopathy (OIR) and assessed at p17. NV quantification was determined by measuring NV tufts and vascular leakage was quantified by measuring [3H]-mannitol leakage from blood vessels into the retina. Gene expression was measured by real-time quantitative (Q)PCR. VEGFR1 and VEGFR2 expressions were up-regulated during CNV pathogenesis. Both MF1 and DC101 significantly suppressed CNV at 50 mg/kg: DC101 suppressed CNV by 73±5% (p<0.0001) and MF1 by 64±6% (p = 0.0002) in a dosage-dependent manner. The combination of MF1 and DC101 enhanced the inhibitory efficacy and resulted in an accumulation of retinal microglia at the CNV lesion. Similarly, both MF1 and DC101 significantly suppressed retinal NV in OIR at 50 mg/kg: DC101 suppressed retinal NV by 54±8% (p = 0.013) and MF1 by 50±7% (p<0.0002). MF1 was even more effective at inhibiting ischemia-induced BRB breakdown than DC101: the retina/lung leakage ratio for MF1 was reduced by 73±24%, p = 0.001 and for DC101 by 12±4%, p = 0.003. The retina/renal leakage ratio for MF1 was reduced by 52±28%, p = 0.009 and for DC101 by 13±4%, p = 0.001. Our study provides further evidence that both VEGFR1 and 2 mediate pathological angiogenesis and vascular leakage in these models of ocular disease and suggests that antagonist antibodies to these receptor tyrosine kinases (RTKs) are potential therapeutic agents.
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