Targeting Platelet-Derived Growth Factor Receptor β+ Scaffold Formation Inhibits Choroidal Neovascularization
Targeting Platelet-Derived Growth Factor Receptor β+ Scaffold Formation Inhibits Choroidal Neovascularization
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DOI：
10.1016/j.ajpath.2016.02.018
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发表时间：
2016-07-01
影响因子：
6
通讯作者：
Marneros, Alexander G.
中科院分区：
文献类型：
--
作者：
Strittmatter, Karin;Pomeroy, Hayley;Marneros, Alexander G.
新生血管性年龄相关性黄斑变性是不可逆失明的最常见原因之一，并表现为脉络膜新生血管（CNV）。抗血管内皮生长因子-A疗法仅部分有效，并且其长期施用可能损害脉络膜毛细血管和视网膜的功能。因此，迫切需要新的治疗靶点。我们已经在激光诱导的CNV模型中观察到，在新血管浸润到血小板衍生生长因子受体β阳性（PDGFR β（+））支架中以形成CNV损伤之前形成该支架，并且该支架限制了新血管形成的程度。基于这些观察，我们假设消融增殖的PDGFR β（+）细胞以防止这种支架的形成可能抑制CNV生长，并为新生血管性年龄相关性黄斑变性提供了一种新的治疗方法。为了检验这一假设，我们在激光损伤后通过独立的不同方法靶向增殖的PDGFR β（+）细胞：i）通过使用诱导型遗传模型特异性抑制增殖的PDGFR β细胞，ii）通过用中和性抗PDGFR β抗体治疗小鼠，iii）通过施用抗PDGF-AB/BB适体，和iv）通过使用小的化学抑制剂方法。结果表明，靶向增殖的PDGFR β（+）细胞的治疗有效地抑制了周细胞样支架的形成，同时减弱了CNV。此外，我们发现在新血管形成之前早期抑制PDGFR β细胞增殖足以抑制支架形成和新血管形成。
Neovascular age-related macular degeneration is among the most common causes of irreversible blindness and manifests with choroidal neovascularization (CNV). Anti-vascular endothelial growth factor-A therapies are only partially effective and their chronic administration may impair functions of the choriocapillaris and retina. Thus, novel therapeutic targets are needed urgently. We have observed in a laser-induced model of CNV that a platelet-derived growth factor receptor beta positive (PDGFR beta(+)) scaffold is formed before infiltration of neovessels into this scaffold to form CNV lesions, and that this scaffold limits the extent of neovascularization. Based on these observations we hypothesized that ablation of proliferating PDGFR beta(+) cells to prevent the formation of this scaffold might inhibit CNV growth and present a novel therapeutic approach for neovascular age-related macular degeneration. To test this hypothesis we targeted proliferating PDGFR beta(+) cells through independent distinct approaches after laser injury: i) by using an inducible genetic model to inhibit specifically proliferating PDGFR beta cells, ii) by treating mice with a neutralizing anti-PDGFR beta antibody, iii) by administering an anti-PDGF-AB/BB aptamer, and iv) by using small chemical inhibitor approaches. The results show that therapeutic targeting of proliferating PDGFR beta(+) cells potently inhibits the formation of the pericyte-like scaffold, with concomitant attenuation of CNV. Moreover, we show that early inhibition of PDGFR beta cell proliferation before neovessel formation is sufficient to inhibit scaffold formation and neovascularization.