Rationale: Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored.

Objective: We have investigated the role of IPMK in regulating angiogenesis.

Methods and Results: Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel–Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood–brain barrier and enhances brain blood vessel permeability.

Conclusions: IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α.

原理：肌醇多磷酸多激酶（IPMK）及其主要产品肌醇五磷酸（IP5）调节多种细胞功能，但它们在血管生物学中的作用尚待探索。

目的：我们研究了IPMK在调节血管生成中的作用。

方法和结果：成纤维细胞中IPMK的删除在体外和体内模型中均诱导血管生成。IPMK缺失引起VEGF（血管内皮生长因子）的大量增加，其介导IPMK对血管生成的调节。IPMK对VEGF的调节需要其催化活性。IPMK主要为核，并调节基因转录。但是，IPMK显然不充当VEGF的转录因子。HIF（缺氧诱导因子）-1α是血管生成的主要决定因素，并诱导VEGF转录。IPMK缺失引起HIF-1α蛋白和VEGF的大量富集。HIF-1α在正常情况下被pVHL（von Hippel–Lindau蛋白）组成型泛素化，然后发生蛋白酶体降解。但是，在IPMK中，pVHL无法识别HIF-1α并使其泛素化KO（敲除）细胞。IP5恢复了HIF-1α和pVHL的相互作用。HIF-1α脯氨酰羟化是pVHL识别的先决条件，在IPMK缺失的细胞中被打断。IP5促进HIF-1α脯氨酰羟基化，从而促进pVHL依赖性的HIF-1α降解。小鼠脑中IPMK的删除会增加HIF-1α/ VEGF水平和血管生成。IPMK KO中增加的VEGF破坏血脑屏障并增强脑血管通透性。

结论： IPMK通过其产物IP5通过抑制VEGF表达来负调节血管生成。IP5通过增强HIF-1α羟基化作用，从而增强HIF-1α的pVHL依赖性降解而起作用。