Experimental and clinical studies over the past few years indicate that ETs are of significance in several human diseases. Their predominant expression in vascular tissues and their multifunctional nature do indeed suggest that alteration of ETs may be involved in diseases affecting both the micro-and macrovasculature. In both animal and human diabetes, ETs have been shown to be upregulated. Hyperglycemia-induced biochemical anomalies such as PKC activation, nonenzymatic glycation, oxidative stress, augmented polyol pathway, and elaboration of various growth factors and cytokines may contribute to alteration of ETs. ETs, in turn, may regulate other vasoactive factors and growth factors leading to changes in both hemodynamic and structural parameters. A schematic outline of ET alteration and its consequences has been depicted in Figure 1. In support of a central role of these multifunctional peptides in diabetes-induced pathogenetic changes, it has been shown that ET-receptor antagonists prevent structural and functional abnormalities in all target organs of chronic diabetic complications in animal models. Based on the available data, ET antagonism may have a potential role in the treatment of these complications.
Basement membrane: A ubiquitous supportive tissue that underlies an epithelium or endothelium. This tissue contains macromolecules such as collagen, fibronectin, laminin, and sulfated proteoglycans.
Extracellular matrix: A meshwork-like substance found within the extracellular space. It provides a supporting structure for cells and regulates cellular events.
Neovascularization: The development of new blood vessels. Neovas-cularization is an important event in tissues where circulation has been impaired by trauma or disease.
Vascular permeability: The property of the vasculature to be pervaded by water and large molecular weight proteins.
Vasoactive factors: Factors that exert an effect on the caliber of blood vessels. These factors include endothelins, angiotensin II, nitric oxide, and prostacyclins.
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10. Khan, Z. A., Cukiernik, M., Gonder, J. R., and Chakrabarti, S. (2004). Oncofetal fibronectin in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 45, 287-295. A recent study that provides the first evidence of altered ECM protein composition in diabetic retinopathy. The study focuses on an aberrant fibronectin molecule, oncofetal fibronectin, which is regulated by endothelins and which may mediate angiogene-sis. The authors conclude that endothelin-induced oncofetal fibronectin could be involved in endothelial cell proliferation.
Dr. Chakrabarti is a professor in the Department of Pathology at the University of Western Ontario, and a pathologist at the London Health Sciences Centre, Canada. His laboratory primarily focuses on structural and functional alterations in diabetic microangiopathy. His work is supported by grants from the Canadian Diabetes Association, Canadian Institutes of Health Research, Heart and Stroke Foundation of Ontario, and Lawson Health Research Institute.
Mr. Zia A. Khan is a graduate student in the Department of Pathology at the University of Western Ontario, Canada.
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