title: Ets-1 transcription is required in tissue factor driven microvessel formation and stabilization.
abstract: Tissue factor (TF) has well-recognized roles as initiator of blood coagulation as well as an intracellular signaling receptor. TF signaling regulates gene transcription and protein translation. Recently, we have shown that TF-induced mature neovessel formation is ultimately driven by CCL2 expression. However, the signaling process induced by TF to promote microvessel formation remains to be determined. This study was designed with the objective to investigate the mechanisms involved in TF-induced neovessel formation. Here, we have identified that Ets-1 expression is a downstream effector of TF signaling. TF-siRNA induced a highly significant reduction in Ets-1 expression levels and in Ets-1/DNA binding while inducing abrogation of microvessel formation. Activation of Ets-1 rescued the effect of TF inhibition and restored microvessel formation confirming the critical role of Ets-1 in TF-induced angiogenesis. VE-cadherin expression, a key regulator of endothelial intercellular junctions, and an Ets-1 target molecule was dependent of TF-inhibition. We show that TF signals through ERK1/2 to activate Ets-1 and induce CCL2 gene expression by binding to its promoter region. We conclude that endothelial cell TF signals through ERK1/2 and Ets-1 to trigger microvessel formation.
authors.affiliation: Cardiovascular Research Center (CSIC-ICCC), Hospital de Sant Pau (UAB), IIB-Sant Pau. CiberOBN, Instituto de Salut Carlos III, C/ Sant Antoni Mª Claret 167, 08025, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Arderiu
authors.forename: Esther
authors.initials: E
authors.lastname: Peña
authors.forename: Rosa
authors.initials: R
authors.lastname: Aledo
authors.forename: Sonia
authors.initials: S
authors.lastname: Espinosa
authors.forename: Lina
authors.initials: L
authors.lastname: Badimon
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism; D002461:Cell Line, Transformed; D018932:Chemokine CCL2 / Q000378:metabolism; D017931:DNA Primers; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000502:physiology*; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D013925:Thromboplastin / Q000502:physiology*; D014158:Transcription, Genetic; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D018932:Chemokine CCL2; D017931:DNA Primers; D050784:Proto-Oncogene Protein c-ets-1; D013925:Thromboplastin; D000099152:Cadherin 5; C494041:ETS1 protein, human