Effects of high glucose on vascular endothelial growth factor expression in vascular smooth muscle cells

Abstract

Vascular endothelial growth factor (VEGF), in addition to its growth-promoting effects on endothelial cells, can also increase vascular permeability and monocyte migration. It has therefore been implicated in the pathogenic neovascularization associated with diabetic retinopathy and atherosclerosis. However, the factors regulating VEGF expression in the vascular wall are not fully understood. In this study, we examined the regulation of VEGF expression in vascular smooth muscle cells (VSMC) by hyperglycemia as well as by angiotensin II (ANG II). We also examined whether the 12-lipoxygenase (12-LO) product 12-hydroxyeicosatetraenoic acid (12-HETE) can alter VEGF expression, since 12-LO products of arachidonic acid have angiogenic properties, and ANG II as well as high glucose (HG, 25 mM) can increase 12-LO activity and expression in VSMC. Studies were carried out in human (HSMC) or porcine VSMC (PSMC), which were cultured for at least two passages under normal glucose (NG, 5.5 mM) or HG conditions. HG culture alone increased the expression of VEGF mRNA and protein in both HSMC and PSMC. Furthermore, ANG II treatment significantly induced VEGF mRNA and protein expression only in VSMC cultured in HG and not NG. In addition, 12-HETE significantly increased VEGF mRNA and protein expression in HSMC cultured in NG as well as in HG. Cells cultured in HG also secreted significantly greater amounts of VEGF into the culture medium. These results suggest that elevated VEGF production under HG conditions may play a role in the accelerated vascular disease observed in diabetes.

Angiotensin converting enzyme inhibiting therapy is associated with lower vitreous vascular endothelial growth factor concentrations in patients with proliferative diabetic retinopathy

“…ACE inhibitors attenuate the formation of angiotensin II and the break-down of bradykinin. Studies in vitro have shown that angiotensin II is able to stimulate the expression of VEGF in bovine retinal pericytes [20], rat heart endothelial cells [26], as well as human vascular smooth muscle [10,16,17] and mesangial cells [18,19]. Moreover, increased concentrations of angiotensin II have been found in the vitreous fluid of patients with proliferative diabetic retinopathy [13,14].…”

“…The mechanism of HIF-1a induction by angiotensin II depends on the production of reactive oxygen species [17]. The observation that hyperglycaemia is required to detect angiotensin II-induced expression of VEGF in cultured smooth muscle cells [16] could also be related to the formation of radicals, because of an altered cellular redox state induced by hyperglycaemia. These in vitro observations agree closely with earlier in vivo observations in rat aorta, namely that infusion of angiotensin II increases the production of superoxide anions by activation of NADPH oxidase, an effect that could be blocked completely by losartan [29,30].…”

“…Diabetic children with increased plasma concentrations of prorenin are at a high risk for the development of retinopathy [15]. In vitro studies indicate that angiotensin II stimulates the secretion of VEGF by vascular smooth muscle cells [10,16,17], mesangial cells [18,19] and pericytes [20]. The induction of VEGF by angiotensin II requires hyperglycaemic [16] or oxidative conditions [17], which are states that accompany diabetes.…”

“…In vitro studies indicate that angiotensin II stimulates the secretion of VEGF by vascular smooth muscle cells [10,16,17], mesangial cells [18,19] and pericytes [20]. The induction of VEGF by angiotensin II requires hyperglycaemic [16] or oxidative conditions [17], which are states that accompany diabetes. In streptozotocin-induced diabetic rats it has been shown that ACE-inhibition reduces the increased concentrations of VEGF mRNA in the retina [21].…”

Putative pathophysiological role of growth factors and cytokines in experimental diabetic kidney disease

“…The most potent stimulator of VEGF that has been found is hypoxia [124,136] but in mesangial cells angiotensin II has been shown to stimulate VEGF, a process that is blocked by co-incubation of losartan, an angiotensin 1 receptor antagonist [133±135]. High glucose concentration has been shown to stimulate VEGF expression in vascular smooth muscle cells [137], probably through PKC stimulation [138]. In addition, phorbol esters stimulate mesangial VEGF production [139] and notably, inhibition of PKC blocks VEGF signalling [140].…”