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Endothelial cytochrome P450 -derived cholesterol limits angiogenesis.

Pedro F Malacarne¹, Melina Lopez¹, Souradeep Chatterjee¹

¹Goethe University, Institute for Cardiovascular Physiology, Frankfurt am Main, Germany; German Centre of Cardiovascular Research (DZHK), Partner Site Rhein Main, Germany.

|July 11, 2026

Summary

Endothelial cytochrome P450 reductase (POR) deficiency impairs cholesterol synthesis, activating SREBP2 and promoting blood vessel growth (angiogenesis) through PI3K/AKT/mTOR signaling.

Keywords:

Angiogenesis Cholesterol Cytochrome P450 oxidoreductase SREBP2

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Area of Science:

Biochemistry
Molecular Biology
Cardiovascular Research

Background:

The cytochrome P450 (CYP450) system, including CYP450 reductase (POR), is crucial for cellular processes.
CYP51A1, a CYP450 isoenzyme, is essential for endogenous cholesterol biosynthesis.
The role of intracellular cholesterol synthesis in endothelial function and angiogenesis is not well understood.

Purpose of the Study:

To investigate the role of endothelial POR in intracellular cholesterol synthesis and its impact on endothelial function.
To elucidate the molecular mechanisms linking POR deficiency, cholesterol metabolism, and angiogenesis.

Main Methods:

Generated CRISPR/Cas9 knockouts of POR in primary human endothelial cells (EC).
Studied an endothelial-specific, tamoxifen-inducible POR knockout mouse model (ecPOR-/-).
Analyzed cholesterol metabolites, SREBP2 activation, angiogenesis assays (spheroids, aortic segments, retinal angiogenesis), RNAseq, and signaling pathway activation (PI3K/AKT/mTOR).

Main Results:

POR deletion in ECs led to lanosterol accumulation and reduced desmosterol, indicating impaired cholesterol synthesis.
POR deficiency promoted basal and VEGF-induced angiogenesis in vitro and in vivo.
Mechanistically, POR deletion activated the SREBP2 pathway and upregulated PI3K/AKT/mTOR signaling, leading to enhanced angiogenesis.

Conclusions:

Endothelial POR and CYP51A1 axis inhibition impairs cholesterol synthesis, activates SREBP2, and enhances angiogenesis.
This study reveals a novel link between intracellular cholesterol metabolism and vascular growth via PI3K/AKT/mTOR signaling.
Targeting the endothelial POR/CYP51A1 pathway may offer new strategies for modulating angiogenesis.