Abstract
Abnormal regulation of angiogenesis in diabetics occurs in a tissue-specific manner: angiogenesis is increased in some tissues (retinal neovascularization) and decreased in others (skin). However, cellular and molecular cell- and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia are poorly understood. We examined cell-type-specific regulation of expression of thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, by high glucose. We previously reported that mRNA and protein levels of TSP-1 were upregulated in response to high glucose in large arteries. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells (MVEC) and retinal pigment epithelial cells (RPE). This downregulation is posttranscriptional: mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of TSP-1 mRNA is upregulated in RPE of diabetic rats, while the protein level is decreased. This cell-type-specific posttranscriptional suppression of TSP-1 production by high glucose in MVEC and RPE is controlled by untranslated regions of TSP-1 mRNA. The cell- and tissue-specific post-transcriptional regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetic patients.
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