Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation

Dec 28, 2017Circulation research

Inositol Polyphosphate Multikinase May Slow New Blood Vessel Growth by Causing Breakdown of a Key Low-Oxygen Protein

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Abstract

Deletion of IPMK in fibroblasts leads to a substantial increase in VEGF levels.

IPMK deletion induces angiogenesis in both in vitro and in vivo models.
The increase in VEGF is mediated by the catalytic activity of IPMK.
HIF-1α protein levels significantly increase following IPMK deletion.
In knockout cells, HIF-1α is not recognized or ubiquitinated by pVHL, preventing its degradation.
IP5 restores the interaction between HIF-1α and pVHL, promoting HIF-1α degradation.
Elevated VEGF levels in IPMK-deleted mouse brain disrupt the blood-brain barrier and increase vessel permeability.

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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 inKO (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 inKO disrupts blood-brain barrier and enhances brain blood vessel permeability. IPMK IPMK

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.

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Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation

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