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Luke Potts, Yi Ren, Lih Kuo, Travis Hein; Endothelium Independence of ROCK-Mediated Retinal Arteriolar Constriction. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3703.
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The interplay of vascular endothelium and smooth muscle is essential for retinal blood flow regulation by changing arteriolar diameter. Since many retinal diseases are associated with endothelial dysfunction along with protein kinase C (PKC) activation and elevated levels of the vasoconstrictor peptide endothelin-1 (ET-1) in the retina, it is important to understand the role of endothelium in modulating vascular diameter under these pathophysiological conditions. We previously reported the importance of Rho kinase (ROCK) in mediating retinal arteriolar constrictions to PKC activation and ET-1 and we herein examined the role of endothelium in these ROCK-mediated vasomotor responses.
To determine whether endothelium has a role in modulating retinal arteriolar constriction to endogenous and exogenous ET-1 and to PKC activation, porcine retinal arterioles were isolated, cannulated and pressurized for functional study. Vasoconstrictions to ET-1 precursor big ET-1 (0.1 µM), ET-1 (0.1 nM), and PKC activator phorbol-12,13-dibutyrate (PDBu, 0.1 µM) with and without the endothelium were examined. Denudation was achieved by intraluminal injection of air and was confirmed immunohistochemically, as well as via demonstration of the absence of dilation to the endothelium-dependent vasodilator bradykinin (10 nM).
Pressurized vessels developed the same degree of basal tone (43±2% of max diameter), which was reversed by ROCK inhibitor H-1152 (1 μM), with or without the endothelium. While the dilation of denuded vessels to endothelium-independent vasodilator sodium nitroprusside remained unaltered, vasoconstriction to endogenous ET-1 via big ET-1 was reduced by 50% and reversed by H-1152. Although the vasoconstrictions to ET-1 and PDBu were not altered by denudation, their vasoconstrictor responses were sensitive to H-1152.
It appears that the development of basal tone in porcine retinal arterioles requires sustained ROCK activation in smooth muscle cells. The endothelium does not modulate basal tone and has little influence on the vasomotor responses to ET-1 and PKC activation under resting conditions. Nonetheless, the endothelium is responsible for a significant portion of overall retinal arteriolar conversion of big ET-1 to ET-1 for vasoconstriction. Moreover, ROCK is a major signaling molecule responsible for vasoconstrictions to ET-1 and PKC activation independent of the endothelium.
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