Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Clin Invest
2004 Jan 01;1132:188-99. doi: 10.1172/JCI19383.
Show Gene links
Show Anatomy links
Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival.
Maes C
,
Stockmans I
,
Moermans K
,
Van Looveren R
,
Smets N
,
Carmeliet P
,
Bouillon R
,
Carmeliet G
.
???displayArticle.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 VEGF(120), VEGF(164), and VEGF(188) 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 VEGF(164) or only VEGF(188) (in VEGF(188/188) mice) was sufficient for metaphyseal development. VEGF(188/188) 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 VEGF(188) 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 VEGF(188/188) mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF(188) isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.
Amling,
Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development.
1997, Pubmed
Amling,
Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development.
1997,
Pubmed
BRASHEAR,
EPIPHYSEAL AVASCULAR NECROSIS AND ITS RELATION TO LONGITUDINAL BONE GROWTH.
1963,
Pubmed
Bachelder,
Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells.
2001,
Pubmed
Bagnard,
Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor.
2001,
Pubmed
Behar,
Semaphorin III is needed for normal patterning and growth of nerves, bones and heart.
1996,
Pubmed
Brighton,
Structure and function of the growth plate.
1978,
Pubmed
Carmeliet,
Mechanisms of angiogenesis and arteriogenesis.
2000,
Pubmed
Cole,
Perivascular cells in cartilage canals of the developing mouse epiphysis.
1985,
Pubmed
Dias,
VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition.
2002,
Pubmed
Flanigan,
Experience with latrogenic pediatric vascular injuries. Incidence, etiology, management, and results.
1983,
Pubmed
Floyd,
Vascular events associated with the appearance of the secondary center of ossification in the murine distal femoral epiphysis.
1987,
Pubmed
Gerber,
VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism.
2002,
Pubmed
Gerber,
VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation.
1999,
Pubmed
Haigh,
Conditional inactivation of VEGF-A in areas of collagen2a1 expression results in embryonic lethality in the heterozygous state.
2000,
Pubmed
Holmbeck,
MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.
1999,
Pubmed
Karsenty,
Reaching a genetic and molecular understanding of skeletal development.
2002,
Pubmed
Kitsukawa,
Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs.
1995,
Pubmed
,
Xenbase
Kronenberg,
Developmental regulation of the growth plate.
2003,
Pubmed
Maes,
Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.
2002,
Pubmed
Miao,
Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165.
1999,
Pubmed
Nakagawa,
Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts.
2000,
Pubmed
Neufeld,
The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis.
2002,
Pubmed
Oosthuyse,
Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.
2001,
Pubmed
Pfander,
HIF-1alpha controls extracellular matrix synthesis by epiphyseal chondrocytes.
2003,
Pubmed
Rivas,
Structural stages in the development of the long bones and epiphyses: a study in the New Zealand white rabbit.
2002,
Pubmed
Robinson,
The splice variants of vascular endothelial growth factor (VEGF) and their receptors.
2001,
Pubmed
Ryan,
HIF-1 alpha is required for solid tumor formation and embryonic vascularization.
1998,
Pubmed
Schipani,
Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival.
2001,
Pubmed
Semenza,
HIF-1: mediator of physiological and pathophysiological responses to hypoxia.
2000,
Pubmed
Soker,
VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding.
2002,
Pubmed
Soker,
Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor.
1998,
Pubmed
Stalmans,
Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms.
2002,
Pubmed
Tomita,
The role of the epiphyseal and metaphyseal circulations on longitudinal growth in the dog: an experimental study.
1986,
Pubmed
Trueta,
The vascular contribution to osteogenesis. III. Changes in the growth cartilage caused by experimentally induced ischaemia.
1960,
Pubmed
Vu,
MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes.
1998,
Pubmed
Walter,
Diminished epiphyseal growth following iatrogenic vascular trauma.
2000,
Pubmed
Wirth,
The blood supply of the growth plate and the epiphysis: a comparative scanning electron microscopy and histological experimental study in growing sheep.
2002,
Pubmed
Zachary,
Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family.
2001,
Pubmed
Zelzer,
Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis.
2002,
Pubmed
Zhou,
Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I.
2000,
Pubmed
