Advanced glycosylation end products stimulate the growth but inhibit the prostacyclin‐producing ability of endothelial cells through interactions with their receptors

Yamagishi, Sho‐ichi; Yamamoto, Yasuhiko; Harada, Shinichi; Hsu, Cheng‐Chin; Yamamoto, Hiroshi

doi:10.1016/0014-5793(96)00279-7

Cited by 52 publications

(43 citation statements)

References 12 publications

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“…As shown in Fig. 5C, 35 S-labeled proteins that migrated to the positions of 18 and 22 kDa, corresponding to VEGF 121 and VEGF 165 , respectively, were immunoprecipitated, and the amounts of these proteins were found to be increased to about 2.5-fold by the AGE treatment.…”

Section: Stimulation Of the Growth Of Microvascular Endothelialmentioning

confidence: 85%

“…the umbilical vein. Though modestly, AGE-BSA caused a consistent increase in cell number and in DNA synthesis of both umbilical and microvasular endothelial cells, the same AGE-BSA concentration (50 g/ml) giving the maximal effect in both cases (35). Lower panels show expression of VEGF receptor genes.…”

Section: Discussionmentioning

confidence: 96%

“…Although this antiserum was partially reactive to carboxymethyllysine, it would seem unlikely that the AGE effect could be accounted for by such glycoxidative biproducts of the Maillard reaction, which might be present in trace amounts in the AGE-BSA preparation, because authentic carboxymethylated BSA added to the culture medium at concentrations from 1 to 100 g/ml failed to stimulate the endothelial cell synthesis of DNA (data not shown). We speculate that the AGE actions on microvascular endothelial cells may require their binding to RAGE, the AGE-specific receptor, as is the case with bovine retinal pericytes (9), human umbilical vein endothelial cells (35), and human pancreatic cancer cells (36).…”

Section: Discussionmentioning

confidence: 99%

“…As shown in this paper, one consequence is angiogenesis that is probably mediated by autocrine VEGF. In addition, the prostacyclin-synthesizing ability of microvascular endothelial cells might be directly inhibited by AGE, as in umbilical endothelial cells (35). Again, the consequence of this would be thrombogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…According to this model, procedures that can halt those events, e.g. inhibition of AGE formation, 3 AGE absorption by immobilized antibodies, antisense RAGE DNA (35,36), prostacyclin analogues, or anti-VEGF neutralizing antibodies would then theoretically help circumvent the development and progression of diabetic microangiopathies.…”

Section: Discussionmentioning

confidence: 99%

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Advanced Glycation End Products-driven Angiogenesis in Vitro

Yamagishi

Yonekura

Yamamoto

et al. 1997

Journal of Biological Chemistry

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260

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This study was undertaken to determine whether and how advanced glycation end products (AGE), senescent macroproteins accumulated in various tissues under hyperglycemic states, cause angiogenesis, the principal vascular derangement in diabetic microangiopathy. We first prepared AGE-bovine serum albumin (BSA) and anti-AGE antiserum using AGE-RNase A. Then AGE-BSA was administered to human skin microvascular endothelial cells in culture, and their growth was examined. The AGE-BSA, but not nonglycated BSA, was found to induce a statistically significant increase in the number of viable endothelial cells as well as their synthesis of DNA. The increase in DNA synthesis by AGE-BSA was abolished by anti-AGE antibodies. AGE-BSA also stimulated the tube formation of endothelial cells on Matrigel. We obtained the following evidence that it is vascular endothelial growth factor (VEGF) that mainly mediates the angiogenic activities of AGE. Glucose and other reducing sugars can react nonenzymatically with the amino groups of proteins to form reversible Schiff bases and, then, Amadori products. These early glycation products undergo further complex reactions such as rearrangement, dehydration, and condensation to become irreversibly crosslinked, heterogeneous fluorescent derivatives termed advanced glycation end products (AGE) 1 (1). The formation and accumulation of AGE in various tissues have been known to progress during normal aging and at an extremely accelerated rate in diabetes mellitus. This has been implicated in the development of diabetic micro-and macro-vascular complications (1), which may account for the disabilities and high mortality rate in patients with this disease (2).Microvessels are composed of only two types of cells, endothelial cells and pericytes, and have been known to show both functional and structural abnormalities during prolonged diabetic exposure, resulting in the deleterious effects on the organs that they supply (3-5). Using pericyte-endothelial cell co-culture systems, we have shown previously that pericytes can not only regulate the growth but also preserve the prostacyclin-producing ability and protect against lipid peroxide-induced injury of endothelial cells (6). This has provided a basis for understanding how diabetic retinopathy develops consequent to "pericyte loss," the earliest histopathological hallmark in diabetic retinopathy (5, 7).Recently, we have found that AGE exert a growth inhibitory effect and a cell type-specific immediate toxicity on pericytes through interactions with their receptor for AGE (RAGE), a cell surface receptor belonging to the immunoglobulin superfamily (8), and have proposed a novel mechanism for pericyte loss (9). The AGE-induced, RAGE-mediated decrease in pericyte number would then indirectly cause angiogenesis (6,9).In the present study, we investigated the effects of AGE on the growth and tube formation of human skin microvascular endothelial cells, the key steps of angiogenesis. We demonstrate that AGE exert angiogenic activities directly on microvasc...

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Section: Stimulation Of the Growth Of Microvascular Endothelialmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 96%