title: cAMP-dependent protein kinase A (PKA) regulates angiogenesis by modulating tip cell behavior in a Notch-independent manner.
abstract: cAMP-dependent protein kinase A (PKA) is a ubiquitously expressed serine/threonine kinase that regulates a variety of cellular functions. Here, we demonstrate that endothelial PKA activity is essential for vascular development, specifically regulating the transition from sprouting to stabilization of nascent vessels. Inhibition of endothelial PKA by endothelial cell-specific expression of dominant-negative PKA in mice led to perturbed vascular development, hemorrhage and embryonic lethality at mid-gestation. During perinatal retinal angiogenesis, inhibition of PKA resulted in hypersprouting as a result of increased numbers of tip cells. In zebrafish, cell autonomous PKA inhibition also increased and sustained endothelial cell motility, driving cells to become tip cells. Although these effects of PKA inhibition were highly reminiscent of Notch inhibition effects, our data demonstrate that PKA and Notch independently regulate tip and stalk cell formation and behavior.
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium Vascular Patterning Laboratory, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium pavel.nedvetsky@vib-kuleuven.be holger.gerhardt@mdc-berlin.de.
authors.forename: Pavel I
authors.initials: PI
authors.lastname: Nedvetsky
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium Vascular Patterning Laboratory, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Xiaocheng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium Vascular Patterning Laboratory, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathivet
authors.affiliation: Vascular Biology Laboratory, London Research Institute - Cancer Research UK, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Aspalter
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium Vascular Patterning Laboratory, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Fabio
authors.initials: F
authors.lastname: Stanchi
authors.affiliation: Department of Anatomy, University of California San Francisco, Genentech Hall, 600 16th Street, San Francisco, CA 94143-2140, USA.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Metzger
authors.affiliation: Department of Anatomy, University of California San Francisco, Genentech Hall, 600 16th Street, San Francisco, CA 94143-2140, USA.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
authors.affiliation: Vascular Patterning Laboratory, Vesalius Research Center, VIB, Leuven, Belgium Vascular Patterning Laboratory, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium Vascular Biology Laboratory, London Research Institute - Cancer Research UK, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3LY, UK Integrative Vascular Biology Lab, Max-Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rössle-Strasse 10, Berlin 13125, Germany DZHK (German Center for Cardiovascular Research), partner site Berlin Berlin Institute of Health (BIH), Berlin, Germany pavel.nedvetsky@vib-kuleuven.be holger.gerhardt@mdc-berlin.de.
authors.forename: Holger
authors.identifier: 0000-0002-3030-0384
authors.initials: H
authors.lastname: Gerhardt
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D012160:Retina / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015027:Zebrafish
chemical_list: D051880:Receptors, Notch; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Angiogenesis; Notch; Retina; Signal transduction; Sprouting; Vascular development