Transforming growth factor-β1 requires NADPH oxidase 4 for angiogenesis in vitro and in vivo.
Bottom Line: In cells from Nox4-deficient mice, TGF-β1-induced cell proliferation, migration and tube formation were abolished.In vivo, TGF-β1 stimulated growth of blood vessels into sponges implanted subcutaneously, and this angiogenesis was markedly reduced in Nox4 knockout mice.Thus, endothelial cells are regulated by a TGF-β1 signalling pathway involving Nox4-derived ROS to promote angiogenesis.
Affiliation: Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, East Melbourne, Victoria, Australia; O'Brien Institute, Fitzroy, Victoria, Australia.Show MeSH
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Mentions: In other studies TGF-β1 has been suggested to promote angiogenesis [32,33]. To explore the functional significance of TGF-β1 in regulation of Nox4, we therefore examined the effect of TGF-β1 on angiogenic responses of endothelial cells in vitro and then in vivo. Formation of capillary-like structures was assessed by plating HUVEC and HMECs on solidified growth factor-reduced Matrigel in the absence of serum. Within 8 hrs, TGF-β1-treated cells formed capillary-like structures more efficiently than untreated cells as shown in representative pictures of HUVEC in Figure5A. Transforming growth factor β1-enhanced capillary-like structure formation was indeed prevented by Adv-Nox4i treatment in HUVEC and HMECs (Fig.5B and C). To confirm that Nox4 is required for the TGF-β1-induced angiogenesis, we also studied MHECs. Similar as in human endothelial cells, TGF-β1 enhanced capillary-like structures in WT mouse-derived MHEC suspended in Matrigel, and this response was abolished in Nox4 KO mouse-derived MHEC (Fig.5D and E). These findings suggest that TGF-β1-induced Nox4 plays a role in the formation of endothelial capillary-like structures by endothelial cells, at least in vitro.
Affiliation: Centre for Eye Research Australia, Department of Ophthalmology, University of Melbourne, East Melbourne, Victoria, Australia; O'Brien Institute, Fitzroy, Victoria, Australia.