BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration.
BMP9/ALK1 inhibits neovascularization in mouse models of age-related macular degeneration.
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DOI：
10.18632/oncotarget.11182
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发表时间：
2016-08-30
期刊：
影响因子：
--
通讯作者：
Larrivée B
中科院分区：
文献类型：
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作者：
Ntumba K;Akla N;Oh SP;Eichmann A;Larrivée B
视网膜相关性黄斑变性（AMD）是工业化国家老龄人口失明的主要原因。目前用于治疗AMD的血管内皮生长因子（VEGF）抑制剂的缺点包括抗性和潜在的严重副作用，需要鉴定新的治疗靶点以调节血管生成。通过内皮Alk 1丝氨酸-苏氨酸激酶受体的BMP 9信号传导调节内皮细胞对VEGF的反应，并在发育过程中促进血管静止和成熟。在此，我们发现BMP 9/Alk 1信号传导抑制与AMD相关的病理性眼部血管生成小鼠模型中的新血管形成。在激光诱导的脉络膜新生血管（CNV）和氧诱导的视网膜病变（OIR）中激活Alk 1信号抑制新生血管形成并减少血管病变的体积。Alk 1信号也被发现干扰血管内皮细胞中的VEGF信号，而BMP 9增强VEGFR 2信号阻断的抑制作用，在OIR和激光诱导的CNV。总之，我们的数据表明，靶向BMP 9/Alk 1有效地防止了AMD模型中新血管的生长，并引入了一种新的方法来改善传统的抗VEGF治疗。
Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development. Here, we show that BMP9/Alk1 signaling inhibits neovessel formation in mouse models of pathological ocular angiogenesis relevant to AMD. Activating Alk1 signaling in laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR) inhibited neovascularization and reduced the volume of vascular lesions. Alk1 signaling was also found to interfere with VEGF signaling in endothelial cells whereas BMP9 potentiated the inhibitory effects of VEGFR2 signaling blockade, both in OIR and laser-induced CNV. Together, our data show that targeting BMP9/Alk1 efficiently prevents the growth of neovessels in AMD models and introduce a new approach to improve conventional anti-VEGF therapies.