PDF(Pubmed)
Abstract：
BACKGROUND: Angiogenesis is critical for forming new blood vessels from antedating vascular vessels. The endothelium is essential for angiogenesis, vascular remodelling and minimisation of functional deficits following ischaemia. The insulin-like growth factor (IGF) family is crucial for angiogenesis. Insulin-like growth factor-binding protein 5 (IGFBP5), a binding protein of the IGF family, may have places in angiogenesis, but the mechanisms are not yet completely understood. We sought to probe whether IGFBP5 is involved in pathological angiogenesis and uncover the molecular mechanisms behind it.
RESULTS: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI.
CONCLUSIONS: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.
RESULTS: IGFBP5 expression was elevated in the vascular endothelium of gastrocnemius muscle from critical limb ischaemia patients and hindlimb ischaemic (HLI) mice and hypoxic human umbilical vein endothelial cells (HUVECs). In vivo, loss of endothelial IGFBP5 (IGFBP5EKO) facilitated the recovery of blood vessel function and limb necrosis in HLI mice. Moreover, skin damage healing and aortic ring sprouting were faster in IGFBP5EKO mice than in control mice. In vitro, the genetic inhibition of IGFBP5 in HUVECs significantly promoted tube formation, cell proliferation and migration by mediating the phosphorylation of IGF1R, Erk1/2 and Akt. Intriguingly, pharmacological treatment of HUVECs with recombinant human IGFBP5 ensued a contrasting effect on angiogenesis by inhibiting the IGF1 or IGF2 function. Genetic inhibition of IGFBP5 promoted cellular oxygen consumption and extracellular acidification rates via IGF1R-mediated glycolytic adenosine triphosphate (ATP) metabolism. Mechanistically, IGFBP5 exerted its role via E3 ubiquitin ligase Von Hippel-Lindau (VHL)-regulated HIF1α stability. Furthermore, the knockdown of the endothelial IGF1R partially abolished the reformative effect of IGFBP5EKO mice post-HLI.
CONCLUSIONS: Our findings demonstrate that IGFBP5 ablation enhances angiogenesis by promoting ATP metabolism and stabilising HIF1α, implying IGFBP5 is a novel therapeutic target for treating abnormal angiogenesis-related conditions.
摘要：
背景：血管生成对于从血管开始形成新血管至关重要。内皮对血管生成至关重要，血管重塑和缺血后功能缺陷的最小化。胰岛素样生长因子（IGF）家族对血管生成至关重要。胰岛素样生长因子结合蛋白5（IGFBP5），IGF家族的一种结合蛋白，可能有血管生成的地方，但是机制还没有完全理解。我们试图探索IGFBP5是否参与病理性血管生成，并揭示其背后的分子机制。
结果：严重肢体缺血患者和后肢缺血（HLI）小鼠以及低氧人脐静脉内皮细胞（HUVECs）的腓肠肌血管内皮中IGFBP5的表达升高。在体内,内皮IGFBP5（IGFBP5EKO）的缺失促进了HLI小鼠血管功能的恢复和肢体坏死。此外，IGFBP5EKO小鼠的皮肤损伤愈合和主动脉环发芽比对照小鼠更快。体外，IGFBP5在HUVECs中的遗传抑制显着促进了管的形成，通过介导IGF1R的磷酸化，细胞增殖和迁移，Erk1/2和Akt。有趣的是，用重组人IGFBP5对HUVEC的药物治疗通过抑制IGF1或IGF2功能而对血管生成产生了对比作用。IGFBP5的遗传抑制通过IGF1R介导的糖酵解三磷酸腺苷（ATP）代谢促进细胞氧消耗和细胞外酸化速率。机械上,IGFBP5通过E3泛素连接酶VonHippel-Lindau（VHL）调节HIF1α稳定性发挥其作用。此外，内皮IGF1R的敲除部分消除了HLI后IGFBP5EKO小鼠的修复作用。
结论：我们的研究结果表明，IGFBP5消融通过促进ATP代谢和稳定HIF1α来增强血管生成，提示IGFBP5是治疗异常血管生成相关病症的新型治疗靶标。
结果：严重肢体缺血患者和后肢缺血（HLI）小鼠以及低氧人脐静脉内皮细胞（HUVECs）的腓肠肌血管内皮中IGFBP5的表达升高。在体内,内皮IGFBP5（IGFBP5EKO）的缺失促进了HLI小鼠血管功能的恢复和肢体坏死。此外，IGFBP5EKO小鼠的皮肤损伤愈合和主动脉环发芽比对照小鼠更快。体外，IGFBP5在HUVECs中的遗传抑制显着促进了管的形成，通过介导IGF1R的磷酸化，细胞增殖和迁移，Erk1/2和Akt。有趣的是，用重组人IGFBP5对HUVEC的药物治疗通过抑制IGF1或IGF2功能而对血管生成产生了对比作用。IGFBP5的遗传抑制通过IGF1R介导的糖酵解三磷酸腺苷（ATP）代谢促进细胞氧消耗和细胞外酸化速率。机械上,IGFBP5通过E3泛素连接酶VonHippel-Lindau（VHL）调节HIF1α稳定性发挥其作用。此外，内皮IGF1R的敲除部分消除了HLI后IGFBP5EKO小鼠的修复作用。
结论：我们的研究结果表明，IGFBP5消融通过促进ATP代谢和稳定HIF1α来增强血管生成，提示IGFBP5是治疗异常血管生成相关病症的新型治疗靶标。
