AIBP-LRP2–mediated HDL uptake restricts CXCR4 <sup>+</sup> stemlike capillary expansion and collateral circulation
The tissue environment governs vascular remodeling, a key determinant of collateral circulation (CC) in ischemic disease, yet the mechanisms driving CC in adults remain unclear. Plasma profiling from patients with peripheral artery disease (PAD) and ischemic murine muscle revealed dysregulated lipid metabolism, including elevated APOA1 binding protein (AIBP), with levels positively correlating with PAD severity. Myeloid cells enriched at CC sites increased AIBP expression postischemia. Genetic deletion of AIBP expanded CXCR4⁺ capillary endothelial cells (CECs) with stemlike and proliferative properties that remodeled into functional collaterals, a process blocked by CXCR4 inhibition. Mechanistically, AIBP bound the endocytic receptor LRP2 to promote endothelial uptake of high-density lipoprotein (HDL)-associated miR-223, a repressor of CXCR4. Disruption of this AIBP-LRP2-HDL-miR-223 axis restored CXCR4 and rescued CC growth. These findings define a two-phase mechanism in which stemlike CECs first expand and then transition to arterial fates, establishing a therapeutic strategy for revascularization in ischemic vascular disease.
Authors
- Yamei Liu (ORCID: https://orcid.org/0009-0008-3126-4638)
- Meilian Yao
- Chuanchang Li (ORCID: https://orcid.org/0000-0001-5915-1119)
- Longhou Fang (ORCID: https://orcid.org/0000-0003-1653-5221)
- Yongping Bai (ORCID: https://orcid.org/0000-0002-6355-5842)
- Xunjie Cheng (ORCID: https://orcid.org/0000-0001-8766-0594)
- Jian Zhang (ORCID: https://orcid.org/0000-0001-9877-1601)
- Dan Wang (ORCID: https://orcid.org/0000-0002-3814-7556)
- Jie Liu (ORCID: https://orcid.org/0000-0002-7441-2417)
- Lisha Liu (ORCID: https://orcid.org/0000-0001-9471-5493)
- Junyu Chen (ORCID: https://orcid.org/0000-0002-3462-7560)
- Xin Luo (ORCID: https://orcid.org/0000-0002-4592-6734)
- Jing Chen (ORCID: https://orcid.org/0000-0001-7442-3741)
- Can Du
- Guogang Zhang (ORCID: https://orcid.org/0000-0002-8678-2167)
- Keyu Lin (ORCID: https://orcid.org/0000-0003-4624-6762)
- Lingping Zhu (ORCID: https://orcid.org/0000-0001-6749-8737)
- Minghong Chen (ORCID: https://orcid.org/0000-0001-6205-9014)
Institutions
- Houston Methodist (US)
- Central South University (CN)
- Changsha Medical University (CN)
- Cornell University (US)
- Third Xiangya Hospital (CN)
- Xiangya Hospital Central South University (CN)
- University of South China (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-15
- DOI
- https://doi.org/10.1126/sciadv.adx7862
- Primary Topic
- Angiogenesis and VEGF in Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00