Driving the Hypoxia-Inducible Pathway in Human Pericytes Promotes Vascular Density in an Exosome-Dependent Manner

Objectives: The mechanisms involved in activating pericytes, cells that ensheath capillaries, to engage in the formation of new capillaries, angiogenesis, remain unknown. In this study, the hypothesis was tested that pericytes could be stimulated to promote angiogenesis by driving the HIF pathway. Methods: Pericytes were stimulated with CoCl2 to activate the HIF pathway. Stimulated pericytes were cocultured with endothelial cells in a wound healing assay and in a 3D collagen matrix assay of angiogenesis. A culture system of spinal cord tissue was used to assess microvascular outcomes after treatment with stimulated pericytes. Pharmaceutical inhibition of exosome production was also performed. Results: Treatment with stimulated pericytes resulted in faster wound healing (1.92 +/- 0.18 fold increase, p < 0.05), greater endothelial cord formation (2.9 +/- 0.14 fold increase, p < 0.05) in cell culture assays, and greater vascular density (1.78 +/- 0.23 fold increase, p < 0.05) in spinal cord tissue. Exosome secretion and the physical presence of stimulated pericytes were necessary in the promotion of angiogenic outcomes. Conclusions: These results elucidate a mechanism that may be exploited to enhance features of angiogenesis in the CNS.