# XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6

## TL;DR

XPNPEP2 helps blood vessel growth by controlling mitochondrial function, and its absence causes issues in blood vessel development and tissue repair.

## Contribution

XPNPEP2's role in regulating angiogenesis through mitochondrial modulation and its interaction with SLC25A6 is newly identified.

## Key findings

- XPNPEP2 deletion in mice caused reduced blood vessel density and impaired wound healing.
- XPNPEP2 deficiency led to dysfunctional mitochondria in endothelial cells.
- XPNPEP2 interacts with SLC25A6 and its inhibition reduces SLC25A6 levels via SIAH1.

## Abstract

X-prolyl aminopeptidase 2 (XPNPEP2), which is abundantly expressed in vascular endothelial cells (ECs), has been reported to be associated with cardiovascular disease and angiogenesis. However, its function in ECs and its involvement in the pathogenesis of angiogenesis remain unclear. In this study, we revealed that XPNPEP2 is essential for EC function and angiogenesis via modulation of mitochondrial function. In vivo, XPNPEP2 deletion led to pathological changes in the pulmonary artery wall and renal tissue, decreased venous blood vessel density in the proximal region of superficial retinal vessels, and significantly slowed wound healing and tumor growth in mice. In vitro, XPNPEP2 deficiency impaired EC proliferation, migration, and tubulogenesis, which was accompanied by diminished mitochondria-associated membranes and dysfunctional mitochondria, including insufficient ATP, excessive mitochondrial reactive oxygen species (mROS), and disrupted respiration chain function. XPNPEP2 was found to interact with SLC25A6. The overexpression of XPNPEP2 restored impaired EC angiogenesis and the reduction in SLC25A6 caused by XPNPEP2 ablation. Moreover, inhibition of XPNPEP2 downregulated SLC25A6 via Siah E3 ubiquitin protein ligase 1 (SIAH1)-mediated degradation. Additionally, attenuated EC angiogenesis was achieved solely by silencing SLC25A6. Our findings highlight that XPNPEP2 regulates angiogenesis via modulation of mitochondrial function, which may represent a new strategy for the treatment of angiogenesis-related diseases.