Journal
FASEB JOURNAL
Volume 34, Issue 1, Pages 1231-1246Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201900866RR
Keywords
angiogenesis-dependent diseases; endothelial progenitor cells; EPC-based therapy; neovascularization; Netrin-4
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Funding
- Korea Research Institute of Bioscience and Biotechnology
- National Research Foundation of Korea
- Ministry of Science, Information & Communication Technology and Future Planning [NRF-2015M3A9C6030280, NRF-2015M3A9C6030284, NRF-2013M3A9B6046566, NRF2019R1A2C1089258, NRF2018R1A2B2006724]
- Research of Korea Centers [2018ER610300]
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Endothelial progenitor cells (EPCs) promote neovascularization and tissue repair by migrating to vascular injury sites; therefore, factors that enhance EPC homing to damaged tissues are of interest. Here, we provide evidence of the prominent role of the Netrin-4 (NTN4)-Unc-5 Netrin receptor B (UNC5B) axis in EPC-specific promotion of ischemic neovascularization. Our results showed that NTN4 promoted the proliferation, chemotactic migration, and paracrine effects of small EPCs (SEPCs) and significantly increased the incorporation of large EPCs (LEPCs) into tubule networks. Additionally, NTN4 prominently augmented neovascularization in mice with hindlimb ischemia by increasing the homing of exogenously transplanted EPCs to the ischemic limb and incorporating EPCs into vessels. Moreover, silencing of UNC5B, an NTN4 receptor, abrogated the NTN4-induced cellular activities of SEPCs in vitro and blood-flow recovery and neovascularization in vivo in ischemic muscle by reducing EPC homing and incorporation. These findings suggest NTN4 as an EPC-based therapy for treating angiogenesis-dependent diseases.
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