Abstract
Hyperglycemia induces defects in angiogenesis without alteration in the expression of major vascular growth factors in the chicken chorioallantoic membrane (CAM) model. A direct negative effect of hyperglycemia on angiogenesis may participate in failures of "therapeutic angiogenesis" trials. Here, we tested the hypothesis that the response to pro-angiogenic molecules such as angiotensin-converting enzyme (ACE), endothelin-1 (ET-1), and vascular endothelial growth factor-A (VEGF) is altered by hyperglycemia. Transfected (Chinese hamster ovary [CHO] or human embryonic kidney [HEK]) cells overexpressing ACE, ET-1, or VEGF were deposed onto the CAM of hyperglycemic or control embryos. The proangiogenic effect was evaluated 3 d later by angiography and histological analyses. Gene expression in response to these factors was assessed by in situ hybridization. Only VEGF overexpression evoked a proangiogenic response in the CAM from hyperglycemic embryos, upregulating the expression of endogenous VEGF, VEGF-R2, and Tie-2, all of them related to activation of endothelial cells. In conclusion, in a model where hyperglycemia does not alter the major vascular growth factor expression, the negative effect of diabetes on capillary density was overcome only by VEGF overexpression, whereas responses to other vasoactive peptides were practically abolished under hyperglycemic conditions.
Highlights
The direct effects of hyperglycemia on angiogenesis, the growth of new capillaries from pre-existing ones, have been differently appreciated and differ according to experimental models
As only HEK and HEK-VEGF cells were able to form nodules upon the hyperglycemic chorioallantoic membrane (CAM), we focused our study on these cells and we investigated 1) the potential differences between control and glucose-treated CAM in the degree of vascularization of the nodules, and 2) the mechanisms involved in the pro-angiogenic responses, such as the regulation of gene expression
Diabetes is associated with abnormal angiogenesis [1]
Summary
The direct effects of hyperglycemia on angiogenesis, the growth of new capillaries from pre-existing ones, have been differently appreciated and differ according to experimental models. Arteriogenesis, a process of formation or remodeling of arteries, is decreased in patients with diabetes [2]. In this context, there has been considerable interest in “therapeutic angiogenesis/arteriogenesis”. Most controlled therapeutic angiogenesis trials have been largely negative and the reasons for these failures have been discussed [4]. A direct negative effect of hyperglycemia on neovascularization may explain in part failure of “therapeutic angiogenesis/ arteriogenesis” trials. Patients with overt diabetes often have been excluded from such trials, patients with modest impairment of glucose tolerance or undiagnosed diabetes were not, and they constitute a significant proportion of the patients with coronary artery disease [5]
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