title: Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression.
abstract: Urokinase-type plasminogen activator (uPA) regulates angiogenesis and vascular permeability through proteolytic degradation of extracellular matrix and intracellular signaling initiated upon its binding to uPAR/CD87 and other cell surface receptors. Here, we describe an additional mechanism by which uPA regulates angiogenesis. Ex vivo VEGF-induced vascular sprouting from Matrigel-embedded aortic rings isolated from uPA knock-out (uPA(-/-)) mice was impaired compared with vessels emanating from wild-type mice. Endothelial cells isolated from uPA(-/-) mice show less proliferation and migration in response to VEGF than their wild type counterparts or uPA(-/-) endothelial cells in which expression of wild type uPA had been restored. We reported previously that uPA is transported from cell surface receptors to nuclei through a mechanism that requires its kringle domain. Intranuclear uPA modulates gene transcription by binding to a subset of transcription factors. Here we report that wild type single-chain uPA, but not uPA variants incapable of nuclear transport, increases the expression of cell surface VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) by translocating to the nuclei of ECs. Intranuclear single-chain uPA binds directly to and interferes with the function of the transcription factor hematopoietically expressed homeodomain protein or proline-rich homeodomain protein (HHEX/PRH), which thereby lose their physiologic capacity to repress the activity of vehgr1 and vegfr2 gene promoters. These studies identify uPA-dependent de-repression of vegfr1 and vegfr2 gene transcription through binding to HHEX/PRH as a novel mechanism by which uPA mediates the pro-angiogenic effects of VEGF and identifies a potential new target for control of pathologic angiogenesis.
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and vstepano@mail.med.upenn.edu.
authors.forename: Victoria
authors.initials: V
authors.lastname: Stepanova
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B152TT, United Kingdom.
authors.forename: Padma-Sheela
authors.initials: PS
authors.lastname: Jayaraman
authors.affiliation: Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Zaitsev
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Lebedeva
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Khalil
authors.initials: K
authors.lastname: Bdeir
authors.affiliation: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B152TT, United Kingdom.
authors.forename: Rachael
authors.initials: R
authors.lastname: Kershaw
authors.affiliation: College of Arts and Sciences, Drexel University, Philadelphia, Pennsylvania 19104.
authors.forename: Kelci R
authors.initials: KR
authors.lastname: Holman
authors.affiliation: Russian Cardiology Research Center, Moscow 121552, Russia, School (Faculty) of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 117192, Russia, and.
authors.forename: Yelena V
authors.initials: YV
authors.lastname: Parfyonova
authors.affiliation: Russian Cardiology Research Center, Moscow 121552, Russia, School (Faculty) of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 117192, Russia, and.
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Semina
authors.affiliation: Russian Cardiology Research Center, Moscow 121552, Russia.
authors.forename: Irina B
authors.initials: IB
authors.lastname: Beloglazova
authors.affiliation: Russian Cardiology Research Center, Moscow 121552, Russia, School (Faculty) of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 117192, Russia, and.
authors.forename: Vsevolod A
authors.initials: VA
authors.lastname: Tkachuk
authors.affiliation: From the Departments of Pathology and Laboratory Medicine and.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: C078492:HHEX protein, human; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D014568:Urokinase-Type Plasminogen Activator
keywords: PRH/HHEX transcription factor; VEGF Receptors; angiogenesis; endothelial cell; nuclear translocation; urokinase plasminogen activator; vascular biology; vascular endothelial growth factor (VEGF)