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Soluble VEGF isoforms are essential for establishingepiphyseal vascularization and regulating chondrocyte development and survival
Christa Maes, … , Roger Bouillon, Geert Carmeliet
Christa Maes, … , Roger Bouillon, Geert Carmeliet
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):188-199. https://doi.org/10.1172/JCI19383.
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Article Bone biology

Soluble VEGF isoforms are essential for establishingepiphyseal vascularization and regulating chondrocyte development and survival

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Abstract

VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF120, VEGF164, and VEGF188 isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF164 or only VEGF188 (in VEGF188/188 mice) was sufficient for metaphyseal development. VEGF188/188 mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF188 isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF188/188 mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF188 isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.

Authors

Christa Maes, Ingrid Stockmans, Karen Moermans, Riet Van Looveren, Nico Smets, Peter Carmeliet, Roger Bouillon, Geert Carmeliet

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Figure 4

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VEGF and VEGF receptor expression. (a) Total VEGF and VEGF188 mRNA expre...
VEGF and VEGF receptor expression. (a) Total VEGF and VEGF188 mRNA expression levels in P1.5 WT and VEGF188/188 femurs were determined by qRT-PCR (n = 12; ***P < 0.001). The total VEGF level of WT mice and the VEGF188 level of VEGF188/188 mice were set at 100%. (b and c) In situ hybridization for VEGF showing (b) P1.5 proximal (prox) and distal (dist) tibia and (c) the knee joint region at E16.5. VEGF mRNA is detected in both hypertrophic and immature chondrocytes. Note increased VEGF expression in VEGF188/188 epiphyses in regions of enhanced EF5 binding (see Figure 2). (d–f) In situ hybridization for the VEGF receptors (d) NRP-1, (e) Flk-1, and (f) Flt-1, in P1.5 tibia. (d) NRP-1 is expressed in the proliferating chondrocyte zone, as evident on WT and peripheral VEGF188/188 sections through proximal tibia. (e and f) Flk-1 and Flt-1 show no detectable expression within the cartilage of WT tibia. Scale bars: 100 μm. 188/188, VEGF188/188.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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