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XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6
Chenxi Yang1,2, Yijun Lu1,3, Yu Xia1
1Department of Nephrology, National Clinical Research Center for Child Health, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Frontiers in Cell and Developmental Biology
|January 23, 2026
Summary
X-prolyl aminopeptidase 2 (XPNPEP2) is crucial for endothelial cell function and blood vessel formation by regulating mitochondrial activity. Its absence impairs blood vessel density and wound healing, offering new therapeutic targets for angiogenesis-related diseases.
Area of Science:
- Biochemistry
- Cell Biology
- Physiology
Background:
- X-prolyl aminopeptidase 2 (XPNPEP2) is expressed in vascular endothelial cells (ECs) and linked to cardiovascular disease and angiogenesis.
- The precise role of XPNPEP2 in ECs and angiogenesis pathogenesis is not fully understood.
Purpose of the Study:
- To elucidate the function of XPNPEP2 in endothelial cells and its role in angiogenesis.
- To investigate the underlying mechanisms of XPNPEP2's involvement in angiogenesis, particularly its connection to mitochondrial function.
Main Methods:
- *In vivo* studies using XPNPEP2 deletion in mice to assess pathological changes and physiological functions.
- *In vitro* experiments on ECs to evaluate proliferation, migration, and tubulogenesis.
- Mitochondrial function assays, including ATP production, mitochondrial reactive oxygen species (mROS) measurement, and respiration chain analysis.
- Analysis of XPNPEP2 interaction with SLC25A6 and the role of Siah E3 ubiquitin protein ligase 1 (SIAH1) in regulating SLC25A6 levels.
Main Results:
- XPNPEP2 deletion in mice caused pulmonary artery wall and renal tissue pathology, reduced venous blood vessel density, and impaired wound healing and tumor growth.
- XPNPEP2 deficiency in vitro led to reduced EC proliferation, migration, and tubulogenesis, associated with mitochondrial dysfunction (low ATP, high mROS, disrupted respiration).
- XPNPEP2 interacts with SLC25A6; XPNPEP2 overexpression restored angiogenesis and SLC25A6 levels, while XPNPEP2 inhibition decreased SLC25A6 via SIAH1-mediated degradation. Silencing SLC25A6 alone attenuated EC angiogenesis.
Conclusions:
- XPNPEP2 is essential for endothelial cell function and angiogenesis through the regulation of mitochondrial function.
- The XPNPEP2-SLC25A6 axis, modulated by SIAH1, plays a critical role in angiogenesis.
- Targeting XPNPEP2 may offer a novel therapeutic strategy for angiogenesis-related diseases.
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