title: Polo-like kinase 2 regulates angiogenic sprouting and blood vessel development.
abstract: Angiogenesis relies on specialized endothelial tip cells to extend toward guidance cues in order to direct growing blood vessels. Although many of the signaling pathways that control this directional endothelial sprouting are well known, the specific cellular mechanisms that mediate this process remain to be fully elucidated. Here, we show that Polo-like kinase 2 (PLK2) regulates Rap1 activity to guide endothelial tip cell lamellipodia formation and subsequent angiogenic sprouting. Using a combination of high-resolution in vivo imaging of zebrafish vascular development and a human umbilical vein endothelial cell (HUVEC) in vitro cell culture system, we observed that loss of PLK2 function resulted in a reduction in endothelial cell sprouting and migration, whereas overexpression of PLK2 promoted angiogenesis. Furthermore, we discovered that PLK2 may control angiogenic sprouting by binding to PDZ-GEF to regulate RAP1 activity during endothelial cell lamellipodia formation and extracellular matrix attachment. Consistent with these findings, constitutively active RAP1 could rescue the endothelial cell sprouting defects observed in zebrafish and HUVEC PLK2 knockdowns. Overall, these findings reveal a conserved PLK2-RAP1 pathway that is crucial to regulate endothelial tip cell behavior in order to ensure proper vascular development and patterning in vertebrates.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Longhou
authors.initials: L
authors.lastname: Fang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhan
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Hegarty
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Division of Cardiology, Department of Medicine, School of Medicine, University of California, Los Angeles, CA, USA; Department of Bioengineering, School of Engineering & Applied Science, University of California, Los Angeles, CA, USA.
authors.forename: Tzung K
authors.initials: TK
authors.lastname: Hsiai
authors.affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA.
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Trejo
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0613J, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: nchi@ucsd.edu.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C403525:RAPGEF2 protein, human; D034741:RNA, Small Interfering; C496126:PLK2 protein, human; D017346:Protein Serine-Threonine Kinases; D020827:rap1 GTP-Binding Proteins
keywords: Angiogenesis; Human umbilical vein endothelial cells; Polo-like kinase 2; Vascular development; Zebrafish