TY - JOUR
T1 - FXa-induced intracellular signaling links coagulation to neoangiogenesis: Potential implications for fibrosis
AU - Borensztajn, Keren
AU - Aberson, Hella
AU - Peppelenbosch, Maikel P.
AU - Spek, C. Arnold
PY - 2009
Y1 - 2009
N2 - Fibrosis represents the end-stage of a broad range of disorders affecting organ function. These disorders are often associated with aberrant angiogenesis, but whether vascular abnormalities during fibrosis are characterized by excessive or diminished neo-vascularization remains questionable. Strikingly, activation of the coagulation cascade is frequently observed in association with the progression of fibroproliferative disorders. As we recently showed that coagulation factor (F)Xa induced fibrotic responses in fibroblasts, we hypothesized that FXa might indirectly induce angiogenesis by triggering fibroblasts to secrete proangiogenic factors. In the present study, we show that although FXa induces p42/44 MAP Kinase phosphorylation in endothelial cells, it has no direct effect on endothelial cell proliferation, protein synthesis and tube formation. In contrast, conditioned medium of fibroblasts stimulated with FXa enhanced endothelial cell proliferation, extra cellular matrix synthesis, wound healing and endothelial tube formation. FXa induced VEGF production by fibroblasts and a VEGF neutralizing antibody blocked the indirect effect of FXa on proliferation and realignment of endothelial cells identifying VEGF as a crucial player in angiogenesis during coagulation factor-induced fibrosis. Overall, our results establish a link between the coagulation cascade and angiogenesis during fibrosis. (C) 2009 Elsevier B.V. All rights reserved
AB - Fibrosis represents the end-stage of a broad range of disorders affecting organ function. These disorders are often associated with aberrant angiogenesis, but whether vascular abnormalities during fibrosis are characterized by excessive or diminished neo-vascularization remains questionable. Strikingly, activation of the coagulation cascade is frequently observed in association with the progression of fibroproliferative disorders. As we recently showed that coagulation factor (F)Xa induced fibrotic responses in fibroblasts, we hypothesized that FXa might indirectly induce angiogenesis by triggering fibroblasts to secrete proangiogenic factors. In the present study, we show that although FXa induces p42/44 MAP Kinase phosphorylation in endothelial cells, it has no direct effect on endothelial cell proliferation, protein synthesis and tube formation. In contrast, conditioned medium of fibroblasts stimulated with FXa enhanced endothelial cell proliferation, extra cellular matrix synthesis, wound healing and endothelial tube formation. FXa induced VEGF production by fibroblasts and a VEGF neutralizing antibody blocked the indirect effect of FXa on proliferation and realignment of endothelial cells identifying VEGF as a crucial player in angiogenesis during coagulation factor-induced fibrosis. Overall, our results establish a link between the coagulation cascade and angiogenesis during fibrosis. (C) 2009 Elsevier B.V. All rights reserved
U2 - https://doi.org/10.1016/j.bbamcr.2009.01.011
DO - https://doi.org/10.1016/j.bbamcr.2009.01.011
M3 - Article
C2 - 19339215
SN - 0167-4889
VL - 1793
SP - 798
EP - 805
JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
IS - 5
ER -