Abstract
Type 1 diabetes is characterized by insulin deficiency, type 2 by both insulin deficiency and insulin resistance: in both conditions, hyperglycaemia is accompanied by an increased cardiovascular risk, due to increased atherosclerotic plaque formation/instabilization and impaired collateral vessel formation. An important factor in these phenomena is the Vascular Endothelial Growth Factor (VEGF), a molecule produced also by Vascular Smooth Muscle Cells (VSMC). We aimed at evaluating the role of high glucose on VEGF-A164 synthesis and secretion in VSMC from lean insulin-sensitive and obese insulin-resistant Zucker rats (LZR and OZR). In cultured aortic VSMC from LZR and OZR incubated for 24 h with d-glucose (5.5, 15 and 25 mM) or with the osmotic controls l-glucose and mannitol, we measured VEGF-A164 synthesis (western, blotting) and secretion (western blotting and ELISA). We observed that: (i) d-glucose dose-dependently increases VEGF-A164 synthesis and secretion in VSMC from LZR and OZR (n = 6, ANOVA p = 0.002–0.0001); (ii) all the effects of 15 and 25 mM d-glucose are attenuated in VSMC from OZR vs. LZR (p = 0.0001); (iii) l-glucose and mannitol reproduce the VEGF-A164 modulation induced by d-glucose in VSMC from both LZR and OZR. Thus, glucose increases via an osmotic mechanism VEGF synthesis and secretion in VSMC, an effect attenuated in the presence of insulin resistance.
Highlights
Diabetes Mellitus is a relevant cause of cardiovascular morbility and mortality: both type 1 diabetes, resulting from insulin deficiency, and type 2 diabetes, characterized by the coexistence of insulin resistance and inadequate insulin secretion, present both microvascular and macrovascular complications [1]
We observed that: (i) in aortic Vascular Smooth Muscle Cells (VSMC) from lean insulin-sensitive Zucker fa/+ rats (LZR), a 24 h incubation with D-glucose increased in a concentration dependent manner Vascular Endothelial Growth Factor (VEGF)-A164 secretion (n = 6, ANOVA p = 0.003 for enzyme-linked immunosorbent assay (ELISA) and p = 0.0001 for western blotting, p < 0.05 with Bonferroni’s analysis); (ii) in aortic VSMC from obese insulin-resistant Zucker fa/fa rats (OZR), the actions of D-glucose on VSMC secretion were already present (n = 6, ANOVA p = 0.0001 for ELISA and p = 0.002 for western blotting), but were attenuated in comparison with those observed in VSMC from LZR (n = 6, p = 0.0001 at 15 mM and 25 mM of D-glucose both for ELISA and for western blotting)
To evaluate whether the effects of high glucose are attributable to the osmotic stress, VSMC from aortas of LZR and OZR were incubated for h with 19.5 mM of the two osmotic controls L-glucose (n = 6) and mannitol (n = 6), a concentrations chosen to reproduce the osmolarity characterizing the experiments with mmol/L D-glucose, obtained by adding 19.5 mM D-glucose to the 5.5 mM
Summary
Diabetes Mellitus is a relevant cause of cardiovascular morbility and mortality: both type 1 diabetes, resulting from insulin deficiency, and type 2 diabetes, characterized by the coexistence of insulin resistance and inadequate insulin secretion, present both microvascular (i.e., retinopathy and nephropathy) and macrovascular (i.e., atherosclerotic coronary, cerebral and peripheral vascular disease) complications [1]. Since VEGF-A is a survival factor for endothelial cells, and a regulator of microvascular permeability and a potent vasodilator, it is considered a key molecule in renal and retinal capillary function [2]. It promotes the formation of post-ischemic collateral vessels and plays a role in wound healing [2]. For all these reasons, changes in synthesis and secretion of VEGF-A are strongly correlated with diabetic vascular complications
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