Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188
Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188
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DOI：
10.1016/s0925-4773(01)00601-3
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发表时间：
2002-02-01
影响因子：
2.6
通讯作者：
Carmeliet, G
中科院分区：
文献类型：
--
作者：
Maes, C;Carmeliet, P;Carmeliet, G
血管内皮生长因子（VEGF）介导的血管生成是骨形成的重要组成部分。为了阐明 VEGF 同工型在软骨内骨形成中的作用，我们检查了仅表达 VEGF(120) 同工型的小鼠（VEGF(120/120) 小鼠）的长骨发育。新生儿 VEGF(120/120) 长骨显示出完全紊乱的血管模式，同时骨小梁体积减少 35%，骨生长减少，生长板肥大软骨细胞区扩大 34%。令人惊讶的是，胚胎后肢在毛细血管侵入之前的阶段表现出骨领形成和肥厚软骨钙化的延迟。 VEGF(120/120)骨中成骨细胞和肥大软骨细胞分化的标志基因的表达水平显着降低。此外，通过给予可溶性受体嵌合蛋白（mFlt-1/Fc）抑制胚胎软骨跖骨培养物中的所有VEGF亚型，延缓了骨化的发生和进展，表明成骨细胞和/或肥大软骨细胞的发育受到损害。破骨细胞和内皮细胞最初侵入 VEGF(120/120) 骨的时间被延迟，这与基质金属蛋白酶 9 表达的降低有关。我们的研究结果表明，VEGF（164）和/或VEGF（188）的表达对于正常软骨内骨发育很重要，不仅介导骨血管化，而且还允许肥大软骨细胞、成骨细胞、内皮细胞和破骨细胞的正常分化。 (C) 2002 Elsevier Science Ireland Ltd. 保留所有权利。
Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF(120) isoform (VEGF(120/120) mice). Neonatal VEGF(120/120) long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF(120/120) bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF(120/120) bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF(164) and/or VEGF(188) is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.