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Ischemia‐induced Netrin‐4 promotes neovascularization through endothelial progenitor cell activation via Unc‐5 Netrin receptor B
Author(s) -
Lee Na Geum,
Jeung In Cheul,
Heo Soon Chul,
Song Jinhoi,
Kim Wooil,
Hwang Byungtae,
Kwon MinGi,
Kim YeonGu,
Lee Jangwook,
Park JongGil,
Shin MinGyeong,
Cho YoungLai,
Son MiYoung,
Bae KwangHee,
Lee SangHyun,
Kim Jae Ho,
Min JeongKi
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201900866rr
Subject(s) - neovascularization , homing (biology) , angiogenesis , progenitor cell , microbiology and biotechnology , paracrine signalling , cancer research , endothelial progenitor cell , netrin , ischemia , medicine , receptor , stem cell , biology , ecology , axon guidance
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.