Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular enclothelial growth factor therapy in multiple models of ocular neovascularization
Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular enclothelial growth factor therapy in multiple models of ocular neovascularization
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DOI：
10.2353/ajpath.2006.050588
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发表时间：
2006-06-01
影响因子：
6
通讯作者：
Shima, David T.
中科院分区：
文献类型：
--
作者：
Jo, Nobuo;Mailhos, Carolina;Shima, David T.
血管内皮生长因子-A（VEGF-A）阻断最近已被验证为抑制癌症和眼部病理中新血管生长的有效策略。然而，一些研究也表明，抗VEGF疗法在治疗已建立的不需要的血管方面可能不那么有效，这表明它们可能变得不那么依赖VEGF-A生存。血管的VEGF-A依赖性可能与血管壁细胞（周细胞或平滑肌细胞）的存在有关。壁细胞向生长中的内皮管的募集受血小板衍生生长因子-B（PDGF-B）信号传导的调节，并且干扰该途径导致内皮细胞-壁细胞相互作用的破坏和壁细胞的损失。我们已经研究了角膜和脉络膜新生血管模型中血管对VEGF-A依赖性的基础，使用试剂（抗VEGF适体和抗PDGFR-β抗体）的组合来抑制VEGF-A和PDGF-B信号传导途径。我们证明，随着时间的推移，新生血管变得难以VEGF-A剥夺。我们还表明，在多种新生血管生长模型中，抑制VEGF-A和PDGF-B信号传导比单独阻断VEGF-A更有效地引起血管消退。这些发现提供了对血管生长因子依赖性的深入了解，并验证了增强目前眼部血管生成疾病治疗的联合治疗策略。
'Vascular endothelial growth factor-A (VEGF-A) blockade has been recently validated as an effective strategy for the inhibition of new blood vessel growth in cancer and ocular pathologies. However, several studies have also shown that anti-VEGF therapy may not be as effective in the treatment of established unwanted blood vessels, suggesting they may become less dependent on VEGF-A for survival. The VEGF-A dependence of vessels may be related to the presence of vascular mural cells (pericytes or smooth muscle cells). Mural cell recruitment to the growing endothelial tube is regulated by platelet-derived growth factor-B (PDGF-B) signaling, and interference with this pathway causes disruption of endothelial cell-mural cell interactions and loss of mural cells. We have investigated the basis of blood vessel dependence on VEGF-A in models of corneal and choroidal neovascularization using a combination of reagents (an anti-VEGF aptamer and an anti-PDGFR-beta antibody) to inhibit both the VEGF-A and PDGF-B signaling pathways. We demonstrate that neovessels become refractory to VEGF-A deprivation over time. We also show that inhibition of both VEGF-A and PDGF-B signaling is more effective than blocking VEGF-A alone at causing vessel regression in multiple models of neovascular growth. These findings provide insight into blood vessel growth factor dependency and validate a combination therapy strategy for enhancing the current treatments for ocular angiogenic disease.