Inhibition of angiogenesis on glycated collagen lattices

Abstract

There is growing evidence that the increased nonenzymatic glycation of various tissues, and the accumulation of advanced glycation endproducts (AGEs), are involved in the complications of diabetes mellitus. Nonenzymatic glycation occurs very slowly in longlived proteins within the extracellular matrix, including basement membrane proteins and tissue collagen. In fact, AGE accumulation in the basement membranes and collagen has been demonstrated in diabetic patients with a significant correlation with the severity of diabetic complications [1±3]. Reducing sugars such as glucose react nonenzymatically with free amino groups of proteins to form a reversible Schiff base which is then rearranged to form a more stable Amadori product. This Amadori product is degraded slowly and irreversibly under physiological condi- Diabetologia (1998) Summary Advanced glycation endproduct (AGE) accumulation in extracellular matrix proteins has been demonstrated in diabetic patients with a significant correlation with the severity of diabetic complications. AGE accumulation induces matrix protein cross-link formation, resulting in an increased stiffness of matrix fibres and the reduction of the susceptibility of matrix proteins to proteolytic degradation. We examined whether glycation-induced collagen cross-linking may affect vascular endothelial cell behaviours such as invasion, proliferation and differentiation, using the in vitro angiogenesis model of capillary-like structure formation in three-dimensional matrices of collagen type I. Endothelial cells cultured on collagen gel with angiogenic factors (the combination of fibroblast growth factor-2 and vascular endothelial growth factor) invaded the underlying collagen matrix, and organized capillary-like cord structures in the gel. We found that endothelial cell invasion into glycated collagen gel was significantly attenuated without any effect on proteinase activity including cell-associated plasminogen activator and matrix metalloproteinase in the conditioned medium. In addition, subsequent capillary-like cord formation was also inhibited in glycated collagen gel. In contrast, endothelial cell proliferation was enhanced on glycated collagen gel with or without angiogenic factors compared with control collagen gel. These results suggest that the structural alterations of extracellular matrix proteins through the glycation-induced crosslink formation affect the interaction between endothelial cell and extracellular matrix, resulting in the impairment of an adequate neovascularization in diabetic patients. [Diabetologia (1998) 41: 491±499]

Vascular factors altered in glucose-treated mesangial cells and diabetic glomeruli. Changes in vascular factors impair endothelial cell growth and matrix

“…36 The differentiation of the HUVEC to form capillaries in vitro is dependent on many factors. These include vascular growth factors (VEGF, angiopoietin-1, angiopoietin-2), 37 integrins, 38 extracellular matrix, 39 and insulin. 40 Since the conditioned medium from the high glucose treated mesangial cells contained an altered mixture of vascular factors, the medium was also tested for its ability to inhibit in vitro capillary formation by the endothelial cells.…”

Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

“…In vitro studies have demonstrated a diminished vascular tube formation in response to growth factors in a glycated collagen matrix. 8 In a hindlimb ischemia model, Tamarat et al demonstrated reduced endogenous angiogenesis in diabetic mice which was reversed by the administration of aminoguanidine, an inhibitor of AGE formation. 9 Second, diabetes is associated with alterations in proangiogenic growth factor signaling.…”

“…4 -7 Second, exposure to chronic hyperglycemia leads to the nonenzymatic glycation of proteins and in particular, glycation of the extracellular matrix has been shown to impair the formation of new blood vessels. 8,9 Lastly, the presence of diabetes is associated with abnormalities in growth factor signaling which have not been well characterized, particularly in the myocardium. 10,11 An important limitation to the study of myocardial angiogenesis in the setting of diabetes is the lack of a validated large animal model that captures the functional, microcirculatory, and molecular abnormalities associated with diabetes, and is suitable for the induction of chronic myocardial ischemia.…”

Receptor for Advanced Glycation End Products Is Involved in Impaired Angiogenic Response in Diabetes

“…The angiogenic role of AGEs in vitro remains somewhat controversial: antiangiogenic (16) or proangiogenic (17). Some reports showed the involvement of AGEs in impaired angiogenic response in diabetic animals in vivo; inhibition of AGE formation in diabetic mice is shown to restore ischemia-induced angiogenesis in peripheral limbs (18), and AGEs inhibition with soluble RAGE can restore angiogenic potential during wound healing in diabetic mice (19).…”