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J. Sheng, A. M. Guo, A.-A. Syed, B. Janic, P. A. Edwards, A. G. Scicli; The CYP4A-20-HETE System in Regulation of Cord Blood Derived Endothelial Progenitor Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2665.
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20-hydroxyeicosatetraenoic acid (20-HETE) is an arachidonic acid metabolite produced by Cytochrome P450 (CYP) ω-hydroxylases. We have reported that 20-HETE is angiogenic and 20-HETE synthase inhibitors decrease and even suppress angiogenesis induced by growth factors. In human, the more critical 20-HETE synthases are CYP4A11/4A22 and CYP4F2. Endothelial progenitor cells (EPC) are an important component of neovascularization processes.
We studied whether the CYP4A-20-HETE system can contribute to the regulation of EPC.
Progenitor cells were isolated from human umbilical cord blood and were identified by AC133 and CD34 expression.
We found that these EPC contained both immuno-reactive CYP4A11 and CYP4F2. RT-PCR showed that the mRNA’s coding for these enzymes were also present. When EPC were incubated with arachidonic acid, they formed and secreted 20-HETE. These results indicate that EPC contain an active CYP-20-HETE system. Furthermore, stimulation with 20-HETE increased EPC proliferation and migration indicating that 20-HETE can influence EPC functions. When matrigel plugs containing 20-HETE were injected sc in nude mice, a marked angiogenic response was observed. To study whether the injection of labeled EPC iv results in their accumulation into the 20-HETE-containing plug, we used iron-labeled EPC and determined the presence of the labeled EPC in the plug by MRI and immunohistochemistry. These labeled EPC accumulate into the site of 20-HETE induced neovascularization, which suggests that 20-HETE may induce the homing of EPC. Tube formation by EC seed in matrigel is an in vitro model of angiogenesis. We found that co-culture of EC and EPC results in the tube formation and this effect was inhibited by inhibitors of cytochrome P450 4A/F ω-hydroxylases and by a 20-HETE competitive antagonist. This suggests that 20-HETE is involved in EPC-induced tube formation.
The results suggest that the CYP4A-20-HETE system is involved in regulation of EPC functions associated to angiogenesis.
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