Doronzo Gabriella, Viretto Michela, Russo Isabella, Mattiello Luigi, Anfossi Giovanni, Trovati Mariella
Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences, San Luigi Gonzaga Faculty of Medicine of the Turin University, San Luigi Gonzaga Hospital, Orbassano (Turin), 10043, Italy.
Int J Mol Sci. 2012;13(8):9478-9488. doi: 10.3390/ijms13089478. Epub 2012 Jul 26.
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-A(164) 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-A(164) synthesis (western, blotting) and secretion (western blotting and ELISA). We observed that: (i) d-glucose dose-dependently increases VEGF-A(164) 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-A(164) 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.
1型糖尿病的特征是胰岛素缺乏，2型糖尿病则是胰岛素缺乏和胰岛素抵抗并存：在这两种情况下，高血糖都会伴随着心血管风险增加，这是由于动脉粥样硬化斑块形成/不稳定增加以及侧支血管形成受损所致。这些现象中的一个重要因素是血管内皮生长因子（VEGF），它也是血管平滑肌细胞（VSMC）产生的一种分子。我们旨在评估高糖对来自瘦型胰岛素敏感和肥胖胰岛素抵抗的 Zucker 大鼠（LZR 和 OZR）的血管平滑肌细胞中 VEGF-A(164) 合成和分泌的作用。在来自 LZR 和 OZR 的培养主动脉血管平滑肌细胞中，用 d-葡萄糖（5.5、15 和 25 mM）或渗透性对照 l-葡萄糖和甘露醇孵育 24 小时后，我们测量了 VEGF-A(164) 的合成（蛋白质免疫印迹法）和分泌（蛋白质免疫印迹法和酶联免疫吸附测定法）。我们观察到：（i）d-葡萄糖剂量依赖性地增加 LZR 和 OZR 的血管平滑肌细胞中 VEGF-A(164) 的合成和分泌（n = 6，方差分析 p = 0.002 - 0.0001）；（ii）与 LZR 相比，15 和 25 mM d-葡萄糖对 OZR 的血管平滑肌细胞的所有作用均减弱（p = 0.0001）；（iii）l-葡萄糖和甘露醇重现了 d-葡萄糖在 LZR 和 OZR 的血管平滑肌细胞中诱导的 VEGF-A(164) 调节。因此，葡萄糖通过渗透机制增加血管平滑肌细胞中 VEGF 的合成和分泌，在存在胰岛素抵抗的情况下这种作用减弱。
