Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy
Uncoupling of vascular endothelial growth factor with nitric oxide as a mechanism for diabetic vasculopathy
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DOI：
10.1681/asn.2005070759
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发表时间：
2006-03-01
影响因子：
13.6
通讯作者：
Johnson, Richard J.
中科院分区：
文献类型：
--
作者：
Nakagawa, Takahiko;Sato, Waichi;Johnson, Richard J.
血管内皮生长因子在血管疾病中的作用是复杂的。血管内皮生长因子(VEGF)的表达在糖尿病血管病变中是有害的，尤其是在肾脏和视网膜。相反，在非糖尿病肾病中，血管内皮生长因子似乎具有肾脏保护作用。血管内皮生长因子发挥其生物效应与一氧化氮(NO)有关，但已知糖尿病患者体内NO生物利用度降低。因此，推测血管内皮生长因子在糖尿病血管病变中的这种不同的生物学作用是由于血管内皮生长因子与一氧化氮的解偶联。血管内皮生长因子以剂量依赖的方式刺激牛主动脉内皮细胞产生NO，这种作用可被高糖或N-奥米伽-硝基-1-精氨酸甲酯(L-NAME)抑制。高糖对血管内皮细胞一氧化氮合酶磷酸化也有抑制作用。有趣的是，高糖和L-NAME都增强了内皮细胞的增殖反应，而这一反应被NO供体阻止。此外，高糖和L-NAME均可刺激血管内皮细胞血管内皮生长因子和血管内皮生长因子受体2(KDR)的表达。这些数据表明，血管内皮细胞生长因子与一氧化氮的解偶联通过KDR途径促进内皮细胞的增殖。与这些发现相一致的是，KDR拮抗剂阻断了这一反应。此外，一个仅与KDR结合的血管内皮生长因子突变体可诱导细胞外信号调节激酶(ERK)的激活，并在此条件下抑制ERK完全阻断内皮细胞的增殖，提示KDR-ERK1/2通路在内皮细胞增殖中起作用。综上所述，高糖导致血管内皮生长因子与一氧化氮解偶联，通过激活KDR-ERK1/2通路促进内皮细胞增殖。这些结果可能为理解糖尿病血管病变的机制提供新的见解。
The role of VEGF in vascular disease is complicated. Vascular endothelial growth factor (VEGF) expression can be deleterious in diabetic vasculopathy, especially in kidney and retina. In contrast, VEGF seems to be renoprotective in nondiabetic renal disease. VEGF exerts it biologic effects in association with nitric oxide (NO), yet it is known that NO bioavailability is reduced in diabetes. Thus, it was hypothesized that this diverse biologic effect of VEGF on diabetic vasculopathy is due to uncoupling of VEGF with NO. VEGF stimulated NO production in a dose-dependent manner in bovine aortic endothelial cells (BAEC), and this was inhibited by either high glucose or N omega-nitro-1-arginine methyl ester (L-NAME) treatment. Endothelial NO synthase phosphorylation by VEGF was also inhibited by high glucose. It is interesting that both high glucose and L-NAME enhanced the proliferative response of endothelial cells, which was prevented by an NO donor. Furthermore, high glucose as well as L-NAME stimulated VEGF and kinase-insert domain receptor (KDR) (VEGF receptor 2) mRNA expression in BAEC. These data suggest that the uncoupling of VEGF with NO enhances endothelial cell proliferation via the KDR pathway. Compatible with these findings, a KDR antagonist blocked this response. In addition, a VEGF mutant, which binds only KDR, induced extracellular signal-regulated kinase (ERK) activation, and inhibition of ERK completely blocked endothelial cell proliferation under this condition, suggesting a role of the KDR-ERK1/2 pathway on endothelial cell proliferation. In conclusion, high glucose causes an uncoupling of VEGF with NO, which enhances endothelial cell proliferation via activation of the KDR-ERK1/2 pathway. These results may provide new insights into the understanding of the mechanism of diabetic vascular disease.