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T. Kamisasanuki, S. Tokushige, K. Kosai, T. Sakamoto; CD9 siRNA Gene Therapy Inhibits Diverse Growth Factors-Induced Angiogenesis in vitro and in vivo. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3131.
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It is evident that anti-angiogenesis is the important treatment strategy for intractable eye disease such as proliferative diabetes retinopathy and age-related macular degeneration because of the significant clinical response of the anti- vascular endothelial growth factor (VEGF) antibody. A definitive physiological and/or pathological role of CD9, a member of tetraspanin superfamily, remains elusive. Because CD9 forms lateral associations with multiple partner proteins, and because CD9 is abundant in endothelial cells, we hypothesize that CD9 may be involved in any functions of endothelial cell, and examined this biological issue and the possibility of its application toward a novel therapeutic strategy.Methods and
Angiogenesis in vitro (Boyden chamber) / Expression levels of endogenous CD9 in the human dermal microvascular endothelial cell (HMVEC) line is high and CD9 overexpression did not affect migration induced by VEGF or hepatocyte growth factor(HGF). By the way, transfection of small interfering RNA (siRNA ) targeted CD9 (2 types) inhibited HMVEC migration and invasion induced by either growth factors and it was dependent on the inhibition level of CD9 expression. Angiogenesis in vivo (rat cornea micropocket assay) / Pellets containing either VEGF or HGF were implanted into cornea and siRNA-CD9 was injected into subconjuctival region twice 6 and 24 hours later. Angiogenesis was inhibited 7 days later. Mechanism / CD9 did not function on the activation of growth factor receptors. Physiological role / CD9 knockdown mildly inhibited HMVEC proliferation in non-stimulation (physiological) condition.
This study identified that CD9 is an essential membrane protein in endothelial cells that can confer angiogenic phenotype in response to growth factors. Moreover, the results, including its efficiency, generality, feasibility and novelty, should lead to a development of a novel therapy for some of angiogenic diseases, including ocular angiogenesis, in future.
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