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T. W. Hein, Z. Yuan, R. H. Rosa, Jr., Y. Ren, L. Kuo; Divergent Roles of Nitric Oxide and Phosphoinositide 3-Kinase/Rho Kinase in Vasoreactivity of Human Retinal Arterioles. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3262. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Although the retinal arteriolar network is the major site of flow regulation, there is sparse information at the single vessel level on how vasomotor function is regulated in the human retina. We have previously reported studies of vasoregulatory mechanisms in porcine retinal arterioles. Herein, we studied the vasoreactivity and underlying vasoactive mechanisms of human retinal arterioles in vitro from eyes donated by patients undergoing enucleation at the Scott & White Eye Institute.
The Scott & White Institutional Review Board approved this human subjects study. Patients undergoing enucleation were approached and asked if they would donate eye tissue that would otherwise be discarded after pathologic examination. Four out of 4 patients (61 ± 8 years old) consented. Retinal arterioles were isolated and pressurized by two independent reservoir systems for flow control. Diameter changes were recorded using videomicroscopic techniques. Cellular localization of signaling proteins was identified by immunofluorescence.
All vessels (n = 8, 2/patient) developed myogenic tone (resting diameter = 45 ± 4 µm, maximum diameter = 66 ± 5 µm) under zero flow condition. Adenosine, bradykinin and histamine evoked dose-dependent dilation with ~80% dilation at the highest doses. A stepwise increase in luminal flow produced graded dilation with ~50% dilation at the highest flow. Nitric oxide synthase (NOS) inhibitor L-NAME nearly abolished dilations to bradykinin and flow, but reduced responses to adenosine and histamine by ~20%. In contrast, endothelin-1 (ET-1) caused dose-dependent constriction. Both myogenic tone and ET-1-induced constriction were blocked by Rho kinase (ROCK) inhibitor Y-27632 or by phosphoinositide 3-kinase (PI3K) inhibitor wortmannin. Endothelial NOS and ROCK-1 were localized to retinal endothelial and vascular smooth muscle layers, respectively.
Isolated human retinal arterioles dilate to endogenous chemicals and increased shear stress in an endothelial NO-dependent manner. Conversely, myogenic tone and ET-1-induced constriction are mediated by activation of a smooth muscle PI3K/ROCK-1 pathway. Interestingly, our previous and present studies disclose similarities in the vasoreactivity and underlying signaling mechanisms between human and porcine retinal arterioles. The information gleaned from our studies could suggest novel therapeutic targets in patients with retinal vascular dysfunction.
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