title: The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1.
abstract: Angiogenesis plays an important role in cancer and in many other human diseases. Vascular endothelial growth factor-A (VEGF-A), the best known angiogenic factor, was originally discovered as a potent vascular permeability factor (VPF), suggesting that other vascular permeabilizing agents, such as histamine and serotonin, might also have angiogenic activity. We recently demonstrated that, like VEGF-A, histamine and serotonin up-regulate the orphan nuclear receptor and transcription factor TR3 (mouse homolog Nur77) and that TR3/Nur77 is essential for their vascular permeabilizing activities. We now report that histamine and serotonin are also angiogenic factors that, at low micromolar concentrations, induce endothelial cell proliferation, migration and tube formation in vitro, and angiogenesis in vivo. All of these responses are mediated through specific histamine and serotonin receptors, are independent of VEGF-A, and are directly dependent on TR3/Nur77. Initially, the angiogenic response closely resembled that induced by VEGF-A, with generation of "mother" vessels. However, after ~10 days, mother vessels began to regress as histamine and serotonin, unlike VEGF-A, up-regulated the potent angiogenesis inhibitor thrombospondin-1, thereby triggering a negative feedback loop. Thus, histamine and serotonin induce an angiogenic response that fits the time scale of acute inflammation.
authors: Department of Pathology, Beth Israel Deaconess Medical Center - Harvard Medical School, Boston, MA 02215, USA.
authors: Liuliang
authors: L
authors: Qin
authors: Dezheng
authors: D
authors: Zhao
authors: Jianfeng
authors: J
authors: Xu
authors: Xianghui
authors: X
authors: Ren
authors: Ernest F
authors: EF
authors: Terwilliger
authors: Sareh
authors: S
authors: Parangi
authors: Jack
authors: J
authors: Lawler
authors: Harold F
authors: HF
authors: Dvorak
authors: Huiyan
authors: H
authors: Zeng
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006632:Histamine / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D019700:Thrombospondin 1; D012701:Serotonin; D006632:Histamine