Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo

Angiogenesis is an ordered process requiring the inter-play of numerous cel lular and humoral factors. Studies over the past 20 years have identified s everal growth factors, cytokines, and enzymes that promote blood vessel for mation. Most have revealed how individual factors promote an angiogenic phe notype in endothelial cells in vitro or contribute to blood vessel formatio n in vivo. However, the fundamental question that remains unanswered is how the cellular microenvironment contributes to angiogenesis. Fibrocytes are a recently characterized mesenchymal cell type isolated from peripheral blo od that rapidly enter subcutaneously implanted wound chambers and sites of tissue injury. Here we describe the induction of an angiogenic phenotype in microvascular endothelial cells in vitro and promotion of angiogenesis in vivo by cultured fibrocytes. Fibrocytes constitutively secrete extracellula r matrix-degrading enzymes, primarily matrix metalloproteinase 9, which pro motes endothelial cell invasion. In addition, fibrocytes secrete several pr oangiogenic factors including VEGF, bFGF, IL-8, PDGF, and hematopoietic gro wth factors that promote endothelial cell migration, proliferation, and/or tube formation. By contrast, they do not produce representative antiangioge nic factors. Finally, both autologous fibrocytes and fibrocyte-conditioned media were found to induce blood vessel formation in vivo using the Matrige l angiogenesis model.