ArticleThe Journal of biological chemistry2016
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.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 74 citations in OpenAlex.
- Article
- Fibrinolysis-unrelated functions of the plasminogen/plasmin system: A gateway to successful parasitism?Current research in parasitology & vector-borne diseases · 2026Review
- Angiogenesis: Biological Mechanisms and In Vitro Models.Annals of biomedical engineering · 2025Review
- Viscoelastic HyA Hydrogel Promotes Recovery of Muscle Quality and Vascularization in a Murine Model of Delayed Rotator Cuff Repair.Advanced healthcare materials · 2025Article
- Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets.Signal transduction and targeted therapy · 2025Review
- Urokinase Plasminogen Activation System Modulation in Transformed Cell Lines.International journal of molecular sciences · 2025Article
- Article
- Navigating tumor angiogenesis: therapeutic perspectives and myeloid cell regulation mechanism.Angiogenesis · 2024Review
- Endothelial PDGF-D contributes to neurovascular protection after ischemic stroke by rescuing pericyte functions.Cellular and molecular life sciences : CMLS · 2024Article
- Herbal Therapies for Cancer Treatment: A Review of Phytotherapeutic Efficacy.Biologics : targets & therapy · 2024Review
- The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment.International journal of molecular sciences · 2023Review
- Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus.International journal of molecular sciences · 2023Article
- The contribution of inflammatory astrocytes to BBB impairments in a brain-chip model of Parkinson's disease.Nature communications · 2023Article
- Fibrotic remodeling and tissue regeneration mechanisms define the therapeutic potential of human muscular progenitors.Bioengineering & translational medicine · 2023Article
- The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression.International journal of molecular sciences · 2023Review
- The Haematopoietically-expressed homeobox transcription factor: roles in development, physiology and disease.Frontiers in immunology · 2023Review
- Article
- Endothelial Dysfunction in the Context of Blood-Brain Barrier Modeling.Journal of evolutionary biochemistry and physiology · 2022Article
- Prognostic significance of the urokinase plasminogen activator system in tissue and serum of dogs with appendicular osteosarcoma.PloS one · 2022Article
- Role of Serine Proteases at the Tumor-Stroma Interface.Frontiers in immunology · 2022Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
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.
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