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P. Thampi, M. B. Grant, A. Baharani, J. Cai, M. E. Boulton; Oxygen Concentration Regulates the Temporal Expression of VEGFR-1, VEGFR-2 and CXCR-4 Receptors on CD14+ Monocytes. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4380.
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Hypoxia-regulated factors play a critical role in the recruitment and differentiation of hematopoietic stem cells in hypoxic tissue. This study characterizes the effect of hypoxia on the temporal expression of growth factor/chemokine receptors on CD14+ a population of cells that can differentiate into endothelial cells and also modulate development of neovascularization.
Human CD14+ cells were cultured in HPGM medium with 10% FBS for 4 and 24 hr under normoxic (5 % O2), hypoxic (0.2 % O2) or hyperoxic (20 % O2) environments supplemented with 5% CO2 and nitrogen. The numbers of VEGFR-1, VEGFR-2 and CXCR4 receptors were analyzed by flow cytometry (FACS). Western blot analysis was used to measure relative levels of these proteins in the total cell lysates and mRNA expression levels were determined by real time RT-PCR.
VEGFR-1, VEGFR-2 and CXCR4 receptors were expressed on CD14+ monocytes as confirmed by FACS and western blot analysis. FACS analysis demonstrated that under normoxia VEGFR-1 and CXCR4 steadily increased by 42% and 120% respectively over 24hr while VEGFR-2 was up regulated by 111% at 4hr and down regulated to initial levels at 24hr (p<0.05). However, when cells were maintained under hypoxia VEGFR-1 levels were 101% higher than under normoxia at 4hr and were reduced by 250% at 24hr. VEGFR-2 expression under hypoxia was increased by 20% over normoxia and then decreased by 81% at 24hr. CXCR4 showed no increase under hypoxia until 24hr however levels remained significantly below that of normoxic controls. Neither VEGFR-1 nor VEGFR-2 showed any changes under hyperoxia but CXCR4 increased at 4hr and then returned to basal levels by 24hr. mRNA expression levels of these receptors were also modulated by oxygen concentration.
Transient changes in the local oxygen environment have a profound effect on growth factor/chemokine receptor expression on this CD14+ precursor population and this supports a molecular mechanism for the regulation of the differentiation and function of this endothelial precursor population in hypoxic tissue.
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