The mechanisms by which hormones regulate retinal vascular circulation are not clear. Recently, a new and potent vasoactive hormone, endothelin, has been described and sequenced from vascular endothelial cells. The endothelin (ET) family consists of at least three hormones which have a vasoconstrictive effect on vascular smooth muscle cells. Recently, evidence has indicated that ET probably has a role in regulating retinal circulation since it has been identified in the retina and retinal vascular cells. Since retinal capillary cells have high affinity and specific receptor for ET-1, ET injected into rabbit vitreous was shown to induce vasoconstriction of retinal vessels. We have recently shown that the expression of ET-1 mRNA is regulated by insulin via its own receptor through a novel mechanism. In addition, we have shown that retinal pericytes have ET-1 receptors of 95 and 65 kD whereas smooth muscle cells only have the 60 kD receptor. Lastly, using image analysis of video fluorescein angiogram, the intravitreal bolus injection of 1 x 10 19 M of ET-1 induced vasoconstriction of retinal arteries and arterioles and increased retinal circulation times for as long as 20 min after infusion. We are proposing to study the following three Specific Aims: la) to determine the regulation of ET-1 in retinal and aortic endothelial cells by insulin at the DNA level; b) to characterize the role of high glucose level and protein kinase C in regulating ET-1 expression; c) to correlate the expression of ET-1 in the retina, aorta and kidney with vascular abnormalities in diabetic rats. 2a) To characterize, purify and sequence the receptors of ET-1 in retinal pericytes; b) to determine the biological effects of ET-1 in pericytes on the stimulation or activation of diacylglycerol, IP3, protein kinase C and calponin. 3) To evaluate the physiological actions of ET on retinal circulation in diabetic and non-diabetic rats. From these studies, we will be able to understand ET's expression and mode of action at the genetic, biochemical, cellular and physiological levels with special focus on its role in the development of retinal vascular dysfunctions in diabetes.

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National Eye Institute (NEI)
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Visual Sciences B Study Section (VISB)
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Joslin Diabetes Center
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Kuroki, Tatsuya; Isshiki, Keiji; King, George L (2003) Oxidative stress: the lead or supporting actor in the pathogenesis of diabetic complications. J Am Soc Nephrol 14:S216-20
Yokota, Tamotsu; Ma, Ronald C; Park, Joong-Yeol et al. (2003) Role of protein kinase C on the expression of platelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes 52:838-45
Veves, A; King, G L (2001) Can VEGF reverse diabetic neuropathy in human subjects? J Clin Invest 107:1215-8
Way, K J; Katai, N; King, G L (2001) Protein kinase C and the development of diabetic vascular complications. Diabet Med 18:945-59
Mori, F; King, G L; Clermont, A C et al. (2000) Endothelin-3 regulation of retinal hemodynamics in nondiabetic and diabetic rats. Invest Ophthalmol Vis Sci 41:3955-62
Meier, M; King, G L (2000) Protein kinase C activation and its pharmacological inhibition in vascular disease. Vasc Med 5:173-85
Park, J Y; Takahara, N; Gabriele, A et al. (2000) Induction of endothelin-1 expression by glucose: an effect of protein kinase C activation. Diabetes 49:1239-48
King, G L; Wakasaki, H (1999) Theoretical mechanisms by which hyperglycemia and insulin resistance could cause cardiovascular diseases in diabetes. Diabetes Care 22 Suppl 3:C31-7
Ishii, H; Koya, D; King, G L (1998) Protein kinase C activation and its role in the development of vascular complications in diabetes mellitus. J Mol Med 76:21-31
Takagi, H; King, G L; Aiello, L P (1998) Hypoxia upregulates glucose transport activity through an adenosine-mediated increase of GLUT1 expression in retinal capillary endothelial cells. Diabetes 47:1480-8

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