Hypoxic Induction of Endothelial Cell Growth Factors in Retinal Cells: Identification and Characterization of Vascular Endothelial Growth Factor (VEGF) as ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

1995-01-01

AUTHORS

David T. Shima, Anthony P. Adamis, Napoleone Ferrara, Kiang-Teck Yeo, Tet-Kin Yeo, Rapheal Allende, Judah Folkman, Patricia A. D’Amore

ABSTRACT

BackgroundNew vessel growth is often associated with ischemia, and hypoxic tissue has been identified as a potential source of angiogenic factors. In particular, ischemia is associated with the development of neovascularization in a number of ocular pathologies. For this reason, we have studied the induction of endothelial cell mitogens by hypoxia in retinal cells.Materials and MethodsHuman retinal pigment epithelium (hRPE) were grown under normoxic and hypoxic conditions and examined for the production of endothelial mitogens. Northern analysis, biosynthetic labeling and immunoprecipitation, and ELISA were used to assess the levels of vascular endothelial growth factor/vascular permeability factor (VEGF) and basic fibroblast growth factor (bFGF), two endothelial cell mitogens and potent angiogenic factors. Soluble receptors for VEGF were employed as competitive inhibitors to determine the contribution of the growth factor to the hypoxia-stimulated mitogen production.ResultsFollowing 6–24 hr of hypoxia, confluent and growing cultures of hRPE increase their levels of VEGF mRNA and protein synthesis. Biosynthetic labeling studies and RT-PCR analysis indicate that the cells secrete VEGF121 and VEGF165, the soluble forms of the angiogenic factor. In contrast, hRPE cultured under hypoxic conditions show reduced steady-state levels of basic fibroblast growth factor (bFGF) mRNA and decreased bFGF protein synthesis. Unlike VEGF, bFGF is not found in conditioned media of hRPE following 24 hr of hypoxia. Using a soluble high-affinity VEGF receptor as a competitive inhibitor of VEGF, we demonstrate that a VEGF-like activity is the sole hypoxia-inducible endothelial mitogen produced by cultured hRPE.ConclusionsFrom this comparison we conclude that hRPE do not respond to hypoxia with a general, nonspecific increase in the overall levels of growth factors, as is seen during cell wounding responses or serum stimulation. The physiological relevance of data from this in vitro model are affirmed by separate studies in an animal model of retinal ischemia-induced ocular neovascularization (1) in which retina-derived VEGF levels have been shown to correlate spatio-temporally with the onset of angiogenesis. Taken together, these data support the hypothesis that the induction of VEGF by hypoxia mediates the rapid, initial angiogenic response to retinal ischemia. More... »

PAGES

182-193

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/bf03401566

DOI

http://dx.doi.org/10.1007/bf03401566

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/8529097


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41 Northern analysis
42 RT-PCR analysis
43 VEGF levels
44 VEGF mRNA
45 VEGF receptors
46 VEGF-like activity
47 VEGF121
48 VEGF165
49 activity
50 analysis
51 angiogenesis
52 angiogenic factors
53 angiogenic response
54 animal models
55 bFGF protein synthesis
56 basic fibroblast growth factor
57 basic fibroblast growth factor mRNA
58 biosynthetic labeling
59 cell growth factor
60 cell mitogens
61 cell wounding responses
62 cells
63 characterization
64 comparison
65 competitive inhibitor
66 conditions
67 contrast
68 contribution
69 culture
70 cultured hRPE
71 cultures of hRPE
72 data
73 development
74 development of neovascularization
75 endothelial cell growth factor
76 endothelial cell mitogen
77 endothelial growth factor
78 endothelial growth factor/vascular permeability factor
79 endothelial mitogen
80 epithelium
81 factor mRNA
82 factor/vascular permeability factor
83 factors
84 fibroblast growth factor
85 fibroblast growth factor (bFGF) mRNA
86 form
87 growth
88 growth factor
89 growth factor mRNA
90 growth factor/vascular permeability factor
91 high-affinity VEGF receptors
92 hr
93 hr of hypoxia
94 hypothesis
95 hypoxia
96 hypoxia-inducible endothelial mitogen
97 hypoxic conditions
98 hypoxic induction
99 hypoxic tissue
100 identification
101 immunoprecipitation
102 increase
103 induction
104 induction of VEGF
105 inhibitors
106 initial angiogenic response
107 ischemia
108 ischemia-induced ocular neovascularization
109 labeling
110 labeling studies
111 levels
112 mRNA
113 materials
114 media of hRPE
115 medium
116 mitogen
117 mitogen production
118 model
119 neovascularization
120 nonspecific increase
121 number
122 ocular neovascularization
123 ocular pathology
124 onset
125 onset of angiogenesis
126 overall level
127 pathology
128 permeability factor
129 physiological relevance
130 pigment epithelium
131 potent angiogenic factor
132 potential source
133 production
134 protein synthesis
135 reasons
136 receptors
137 relevance
138 response
139 retina-derived VEGF levels
140 retinal cells
141 retinal ischemia
142 retinal ischemia-induced ocular neovascularization
143 retinal pigment epithelium
144 separate studies
145 serum stimulation
146 sole hypoxia-inducible endothelial mitogen
147 soluble form
148 soluble high-affinity VEGF receptor
149 soluble receptor
150 source
151 spatio
152 steady-state levels
153 stimulation
154 study
155 synthesis
156 tissue
157 vascular endothelial growth factor
158 vascular endothelial growth factor/vascular permeability factor
159 vascular permeability factor
160 vessel growth
161 wounding response
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