title: Hepatoma-derived growth factor-related protein-3 is a novel angiogenic factor.
abstract: Hepatoma-derived growth factor-related protein-3 (Hdgfrp3 or HRP-3) was recently reported as a neurotrophic factor and is upregulated in hepatocellular carcinoma to promote cancer cell survival. Here we identified HRP-3 as a new endothelial ligand and characterized its in vitro and in vivo functional roles and molecular signaling. We combined open reading frame phage display with multi-round in vivo binding selection to enrich retinal endothelial ligands, which were systematically identified by next generation DNA sequencing. One of the identified endothelial ligands was HRP-3. HRP-3 expression in the retina and brain was characterized by Western blot and immunohistochemistry. Cell proliferation assay showed that HRP-3 stimulated the growth of human umbilical vein endothelial cells (HUVECs). HRP-3 induced tube formation of HUVECs in culture. Wound healing assay indicated that HRP-3 promoted endothelial cell migration. HRP-3 was further confirmed for its in vitro angiogenic activity by spheroid sprouting assay. HRP-3 extrinsically activated the extracellular-signal-regulated kinase ½ (ERK1/2) pathway in endothelial cells. The angiogenic activity of HRP-3 was independently verified by mouse cornea pocket assay. Furthermore, in vivo Matrigel plug assay corroborated HRP-3 activity to promote new blood vessel formation. These results demonstrated that HRP-3 is a novel angiogenic factor.
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Michelle E
authors.initials: ME
authors.lastname: LeBlanc
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Weiwen
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Nevada Las Vegas, Las Vegas, Nevada, United States of America.
authors.forename: Nora B
authors.initials: NB
authors.lastname: Caberoy
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America; Department of Ophthalmology, Zhongshan Hospital of Fudan University, Shanghai, China.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Chen
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Feiye
authors.initials: F
authors.lastname: Guo
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alvarado
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Chen
authors.initials: C
authors.lastname: Shen
authors.affiliation: Dept. of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Dept. of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Dept. of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Zhao-Jun
authors.initials: ZJ
authors.lastname: Liu
authors.affiliation: Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Webster
authors.affiliation: Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami School of Medicine, Miami, Florida, United States of America; Vascular Biology Institute, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012160:Retina / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D018797:Cell Cycle Proteins; C402392:Hdgfl3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D048049:Extracellular Signal-Regulated MAP Kinases