title: Circulating fibrocytes stabilize blood vessels during angiogenesis in a paracrine manner.
abstract: Accumulating evidence supports that circulating fibrocytes play important roles in angiogenesis. However, the specific role of fibrocytes in angiogenesis and the underlying mechanisms remain unclear. In this study, we found that fibrocytes stabilized newly formed blood vessels in a mouse wound-healing model by inhibiting angiogenesis during the proliferative phase and inhibiting blood vessel regression during the remodeling phase. Fibrocytes also inhibited angiogenesis in a Matrigel mouse model. In vitro study showed that fibrocytes inhibited both the apoptosis and proliferation of vascular endothelial cells (VECs) in a permeable support (Transwell) co-culture system. In a three-dimensional collagen gel, fibrocytes stabilized the VEC tubes by decreasing VEC tube density on stimulation with growth factors and preventing VEC tube regression on withdrawal of growth factors. Further mechanistic investigation revealed that fibrocytes expressed many prosurvival factors that are responsible for the prosurvival effect of fibrocytes on VECs and blood vessels. Fibrocytes also expressed angiogenesis inhibitors, including thrombospondin-1 (THBS1). THBS1 knockdown partially blocked the fibrocyte-induced inhibition of VEC proliferation in the Transwell co-culture system and recovered the fibrocyte-induced decrease of VEC tube density in collagen gel. Purified fibrocytes transfected with THBS1 siRNA partially recovered the fibrocyte-induced inhibition of angiogenesis in both the wound-healing and Matrigel models. In conclusion, our findings reveal that fibrocytes stabilize blood vessels via prosurvival factors and anti-angiogenic factors, including THBS1.
authors.affiliation: Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Jinqing
authors.initials: J
authors.lastname: Li
authors.affiliation: Cell and Developmental Biology Department, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Hong
authors.initials: H
authors.lastname: Tan
authors.affiliation: Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Yuejun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Lisa
authors.initials: L
authors.lastname: Samuelson
authors.affiliation: Department of Plastic and Burn Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: yuyong@fmmu.edu.cn.
authors.forename: Xueyong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Caibin
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: David A
authors.initials: DA
authors.lastname: Gerber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D004338:Drug Combinations; D042783:Endothelial Cells / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D011509:Proteoglycans / Q000378:metabolism; D019700:Thrombospondin 1 / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
chemical_list: D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D019700:Thrombospondin 1; C059485:matrigel; D003094:Collagen