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Title: The role of TRPV1 and TRPV4 channels in retinal angiogenesis
Author: O'Leary, Caitriona
ISNI:       0000 0004 6060 093X
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Abnormal angiogenesis is a key pathological process associated with many diseases such as metastatic cancer, atherosclerosis, and sight-threatening disorders including proliferative diabetic retinopathy, neovascular age-related macular degeneration, and retinopathy of prematurity. Calcium signalling is fundamental for many endothelial functions including the regulation of blood vessel tone, barrier selectivity and angiogenesis. Calcium influx has been implicated in retinal endothelial cell angiogenic response, but the molecular identity of the underlying calcium channels remains to be fully elucidated. In the present study we have investigated the role of the calcium permeable channels TRPV1 and TRPV4 in retinal angiogenesis both in vitro an in vivo. Both mRNA and protein expression of TRPV1 and TRPV4 were initially confirmed in RMECs using PCR and western blotting experiments, functional channel expression was confirmed using whole cell patch clamp techniques. Pharmacological inhibition of TRPV1 and TRPV4 channels reduced angiogenesis in vitro via modulation of tubulogenesis. HGF-stimulated angiogenesis was found to be sensitive to both TRPV1 and TRPV4 inhibition, but channel inhibition had no effect on VEGF or FGF stimulated angiogenesis in vitro. Inhibition of both channels in vivo reduced hypoxia-dependent retinal neovascularisation and promoted normal therapeutic angiogenesis in an oxygen-induced retinopathy mouse model. TRPV1 inhibition was found to downregulate the mRNA expression of TNF-alpha in vivo, whilst TRPV4 inhibition had no effect. TRPV1 and TRPV4 channels were also found to form functional heterotetrameric channels in retinal endothelial cells in vitro. This study provides evidence for TRPV1 and TRPV4 channels as effective therapeutic targets in retinal angiogenesis both in vitro and in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available