Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 35, Issue 9, Pages 2020-2031Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.115.306142
Keywords
activin receptors; endothelial cells; endothelial progenitor cells; growth differentiation factor 2; ischemia; neovascularization; pathologic
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Funding
- National Research Foundation of Korea (NRF) - Ministry of Education, Science, and Technology [NRF-2015R1A2A1A05001859, NRF-2013M3A9B6046563, NRF-2011-0019267]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute - Ministry of Health & Welfare, Republic of Korea [A111345]
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Objective Modulating endothelial progenitor cells (EPCs) is essential for therapeutic angiogenesis, and thus various clinical trials involving EPCs are ongoing. However, the identification of environmental conditions and development of optimal methods are required to accelerate EPC-driven vasculogenesis. Approach and Results We evaluated gene expression profiles of cord blood-derived EPCs and endothelial cells to identify the key factors in EPCendothelial cell differentiation and to show that transforming growth factor- family members contribute to EPC differentiation. The expression levels of activin receptor-like kinase 1 (ALK1) and its high-affinity ligand, bone morphogenetic protein 9 (BMP9) were markedly changed in EPCendothelial cell differentiation. Interestingly, BMP9 induced EPCendothelial cell differentiation and EPC incorporation into vessel-like structures by acting on ALK1 expressed on EPCs in vitro. BMP9 also induced neovascularization in mice with hindlimb ischemia by increasing vessel formation and the incorporation of EPCs into vessels. Conversely, neovascularization was impaired when ALK1 signaling was blocked. Furthermore, EPCs exposed to either short- or long-term BMP9 stimulation demonstrated these functions in EPC-mediated neovascularization. Conclusions Collectively, our results indicated that BMP9/ALK1 augmented vasculogenesis and angiogenesis, and thereby enhanced neovascularization. Thus, we suggest that BMP9/ALK1 may improve the efficacy of EPC-based therapies for treating ischemic diseases.
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