An antiangiogenic neurokinin-B/thromboxane A2 regulatory axis.
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.
Pal
Saumen
S
Department of Pharmacology, University of Wisconsin Medical School, Madison, WI 53706, USA.
Wu
Jing
J
Murray
Justin K
JK
Gellman
Samuel H
SH
Wozniak
Michele A
MA
Keely
Patricia J
PJ
Boyer
Meghan E
ME
Gomez
Timothy M
TM
Hasso
Sean M
SM
Fallon
John F
JF
Bresnick
Emery H
EH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D015287:Neurokinin B / Q000494:pharmacology / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013928:Thromboxane A2 / Q000494:pharmacology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D020533:Angiogenesis Inhibitors; D018377:Neurotransmitter Agents; D042461:Vascular Endothelial Growth Factor A; D013928:Thromboxane A2; D015287:Neurokinin B; D040262:Receptors, Vascular Endothelial Growth Factor; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine