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

Abstract

Angiogenesis is an ordered process requiring the inter-play of numerous cellular and humoral factors. Studies over the past 20 years have identified several growth factors, cytokines, and enzymes that promote blood vessel formation. Most have revealed how individual factors promote an angiogenic phenotype in endothelial cells in vitro or contribute to blood vessel formation 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 blood 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 extracellular matrix-degrading enzymes, primarily matrix metalloproteinase 9, which promotes endothelial cell invasion. In addition, fibrocytes secrete several proangiogenic factors including VEGF, bFGF, IL-8, PDGF, and hematopoietic growth factors that promote endothelial cell migration, proliferation, and/or tube formation. By contrast, they do not produce representative antiangiogenic factors. Finally, both autologous fibrocytes and fibrocyte-conditioned media were found to induce blood vessel formation in vivo using the Matrigel angiogenesis model.

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

“…Although T cells are not critical to the development of CAIA, T cell activation alters synovial thickness in CIA (33) and may play a regulatory role in CAIA (34). Fibrocytes also directly affect endothelial cells and promote angiogenesis (35), potentially augmenting an inflammatory response.…”

Role of tissue stroma in cancer cell invasion

“…TGF-β upregulates α-SMA expression in fibrocytes and transdifferentiates them into myofibroblasts ( Figure 1) [132]. Moreover, fibrocytes induce migration, proliferation, and capillary tube formation in cultured endothelial cells and promote angiogenesis in vivo [133].…”

TNF-α–stimulated fibroblasts secrete lumican to promote fibrocyte differentiation

“…Fibrocytes express markers of both hematopoietic cells (CD34, CD45, FcγR, LSP-1, MHC class II) and stromal cells (collagens, fibronectin, and matrix metalloproteases) (2,3,(12)(13)(14). Fibrocytes also promote angiogenesis by secreting VEGF, bFGF, IL-8, and PDGF (15). A key question about fibrocyte differentiation and fibrosis is why fibrocytes are readily observed in fibrotic lesions, but are rarely observed in healthy tissues (3,10,(16)(17)(18)(19).…”

“…In fibrotic lesions, tissue-resident fibroblasts proliferate and produce excessive amounts of extracellular matrix (ECM) that distorts tissue architecture, leading to tissue destruction (21,22). Fibrocytes secrete a variety of cytokines including IL-13, TGF-β, CTGF, and TNF-α that promote the proliferation, migration, and extracellular matrix production by the local fibroblasts (15,(23)(24)(25)(26). Conversely, fibroblasts secrete a variety of factors that promote leukocyte entry, survival, and retention during inflammation (27)(28)(29)(30).…”