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M. Ramos-Lopez, T. Hirose, K. Lashkari; Hepatocyte Growth Factor Receptor is Selectively Activated in the Vascular Compartment of Stage 5 Retinopathy of Prematurity . Invest. Ophthalmol. Vis. Sci. 2003;44(13):566.
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Purpose: We have previously shown that hepatocyte growth factor participates in advanced ROP. In this study we localize the distribution of activated (phosphorylated) hepatocyte growth factor receptor-(HGFR/Met) in pre-retinal neovascular membranes from patients with stage 5 ROP. Methods: Neovascular membranes collected from 15 patients with stage 5 ROP (ages, 6-12 months) undergoing open-sky vitrectomy were subjected to frozen sectioning for immunohistochemistry and collagenase digestion for establishment of cell cultures. Double-fluorescence immunohistochemistry was performed using phospho-specific antibodies (phosphotyrosine 1313 and 1365) that recognize the phosphorylated form of HGFR/Met, as well antibodies against total HGFR/met, VEGFR-2, endothelial cell markers (CD31, VE-Cadherin), immature endothelial cell markers (CD34, Tal-1 and AC133/CD133) and astrocytes (GFAP). Results: Although HGFR/Met was expressed in both the astrocytic and vascular components of these membranes, phosphorylated (p)HGFR/Met was selectively identified within three distinct endothelial cell compartments: pHGFR/Met colocalized with (1) CD31+/VE-Cadherin+/CD34-/CD133- endothelial cells associated with mature blood vessels, (2) CD34+/Tal-1+/CD31+/- endothelial cells representing early, immature blood vessels on the retinal side of the membrane, and. (3) individual stromal cells expressing CD34+/AC133+/CD31-, probably representing endothelial cell precursors. In vitro activation of cultured endothelial cells with exogenous rHGF exhibited profound biological reponses including increased motility, proliferation and cell maturation. Conclusions: HGFR/Met signaling exhibits biological responses and is intimately involved in the maturation steps of endothelial cells that contribute to the formation of neovascular membranes associated with stage 5 ROP.
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