Ciclopirox olamine promotes the angiogenic response of endothelial cells and mesenchymal stem cells

BACKGROUND: Prolyl hydroxylase inhibitors (PHIS) are promising compounds to promote angiogenesis by stabilizing hypoxia-inducible factor-1 alpha (HIF-1 alpha), a master regulator of angiogenesis. Increased HIF-1 alpha presence induces expression of proangiogenic genes such as vascular endothelial growth factor (VEGF). OBJECTIVE: We investigated the pharmacological induction of hypoxia via the PHI ciclopirox olamine (CPX) as angiogenesis strategy on human dermal microvascular endothelial cell (hd-mvEC) spheroids directly and indirectly via activating human mesenchymal stem cells (hMSCs). METHODS: HMSCs were isolated from bone marrow and hd-mvECs from foreskin biopsies. MSC-conditioned medium after CPX stimulation (MSC-CM CPX) was analyzed by VEGF ELISA and Proteome Profiler (TM) Human Angiogenesis Array. Direct stimulation with CPX and indirect stimulation via MSC-CM CPX were compared in sprouting assays of hd-mvEC spheroids. RESULTS: Direct stimulation with CPX significantly increased sprouting of hd-mvEC spheroids. MSC-CM CPX also induced sprouting from hd-mvEC spheroids, which was mediated by angiogenic VEGF and other proangiogenic factors that had been produced by stimulated hMSCs. CONCLUSIONS: The stimulation with CPX increased the proangiogenic response of hd-mvECs and hMSCs. The direct stimulation of hd-mvECs with CPX has the potential to replace external VEGF supplementation. Thus, CPX can induce angiogenesis in ECs even in the absence of auxiliary cells demonstrating a promising proangiogenic approach.