Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis.
The requirement for notch signaling during vascular development is well-documented but poorly understood. Embryonic and adult endothelial cells (EC) express notch and notch ligands; however, the necessity for cell-autonomous notch signaling during angiogenesis has not been determined. During angiogenesis, EC display plasticity, whereby a subset of previously quiescent cells loses polarity and becomes migratory. To investigate the role of notch in EC, we have used a three-dimensional in vitro system that models all of the early steps of angiogenesis. We find that newly forming sprouts are composed of specialized tip cells that guide the sprout and trunk cells that proliferate and rearrange to form intercellular lumens. Furthermore, we find that notch acts cell-autonomously to suppress EC proliferation, thereby regulating tube diameter. In addition, when notch signaling is blocked, tip cells divide, and both daughter cells take on a tip cell phenotype, resulting in increased branching through vessel bifurcation. In contrast, notch signaling is not required for re-establishment of EC polarity or for lumen formation. Thus, notch is used reiteratively and cell-autonomously by EC to regulate vessel diameter, to limit branching at the tip of sprouts, and to establish a mature, quiescent phenotype.
Sainson
Richard C A
RC
Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California 92612, USA.
Aoto
Jason
J
Nakatsu
Martin N
MN
Holderfield
Matthew
M
Conn
Erin
E
Koller
Erich
E
Hughes
Christopher C W
CC
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D001808:Blood Vessels / Q000033:anatomy & histology; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002196:Capillaries / Q000033:anatomy & histology / Q000254:growth & development; D002219:Carbamates / Q000494:pharmacology; D002455:Cell Division; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004815:Epidermal Growth Factor / Q000235:genetics; D005456:Fluorescent Dyes; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D016376:Oligonucleotides, Antisense; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology
D002135:Calcium-Binding Proteins; D002219:Carbamates; D004151:Dipeptides; D005456:Fluorescent Dyes; D036341:Intercellular Signaling Peptides and Proteins; C410009:L 685458; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D016376:Oligonucleotides, Antisense; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D004815:Epidermal Growth Factor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human