Prolyl hydroxylase inhibitors (PHIs) are promising compounds to promote angiogenesis by stabilizing hypoxia-inducible factor-1α (HIF-1α), a master regulator of angiogenesis. Increased HIF-1α 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™ 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.
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