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PMID: 17000881 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

An antiangiogenic neurokinin-B/thromboxane A2 regulatory axis.

The Journal of cell biology ·Vol. 174 ·No. 7 ·2006-09-25 ·Pages 1047-58

Pal S, Wu J, Murray JK, Gellman SH, Wozniak MA, Keely PJ, Boyer ME, Gomez TM, Hasso SM, Fallon JF, Bresnick EH

Abstract

Establishment of angiogenic circuits that orchestrate blood vessel development and remodeling requires an exquisite balance between the activities of pro- and antiangiogenic factors. However, the logic that permits complex signal integration by vascular endothelium is poorly understood. We demonstrate that a "neuropeptide," neurokinin-B (NK-B), reversibly inhibits endothelial cell vascular network assembly and opposes angiogenesis in the chicken chorioallantoic membrane. Disruption of endogenous NK-B signaling promoted angiogenesis. Mechanistic analyses defined a multicomponent pathway in which NK-B signaling converges upon cellular processes essential for angiogenesis. NK-B-mediated ablation of Ca2+ oscillations and elevation of 3'-5' [corrected] cyclic adenosine monophosphate (cAMP) reduced cellular proliferation, migration, and vascular endothelial growth factor receptor expression and induced the antiangiogenic protein calreticulin. Whereas NK-B initiated certain responses, other activities required additional stimuli that increase cAMP. Although NK-B is a neurotransmitter/ neuromodulator and NK-B overexpression characterizes the pregnancy-associated disorder preeclampsia, NK-B had not been linked to vascular remodeling. These results establish a conserved mechanism in which NK-B instigates multiple activities that collectively oppose vascular remodeling.

MeSH Terms
1-Methyl-3-isobutylxanthine/pharmacology Angiogenesis Inhibitors/pharmacology,physiology Animals Calcium/metabolism Calcium Signaling/drug effects Cell Line Cell Movement/drug effects Chick Embryo Chorioallantoic Membrane/blood supply,drug effects Down-Regulation/drug effects Drug Synergism Endothelial Cells/drug effects,physiology Mice Models, Biological Muscle, Smooth, Vascular/physiology Neurokinin B/pharmacology,physiology Neurotransmitter Agents/pharmacology,physiology Receptors, Vascular Endothelial Growth Factor/physiology Signal Transduction/drug effects,physiology Thromboxane A2/pharmacology,physiology Vascular Endothelial Growth Factor A/physiology
Chemicals
Angiogenesis Inhibitors Neurotransmitter Agents Vascular Endothelial Growth Factor A Thromboxane A2 Neurokinin B Receptors, Vascular Endothelial Growth Factor Calcium 1-Methyl-3-isobutylxanthine
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Pal Saumen
Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53706, USA.
Wu Jing
Murray Justin K
Gellman Samuel H
Wozniak Michele A
Keely Patricia J
Boyer Meghan E
Gomez Timothy M
Hasso Sean M
Fallon John F
Bresnick Emery H
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200603152
Published
2006-09-25
Pages
1047-58
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2064395
Subset
IM
Grants
NIGMS NIH HHS · T32 GM08349 · United States
NINDS NIH HHS · R01 NS041564 · United States
NIDDK NIH HHS · R01 DK050107 · United States
NIGMS NIH HHS · R01 GM056414 · United States
NIGMS NIH HHS · T32 GM008349 · United States
NICHD NIH HHS · R01 HD032551 · United States
NIGMS NIH HHS · GM56414 · United States
NIDDK NIH HHS · R37 DK050107 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1083/jcb.200603152 PMC Full Text View journal details
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