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A correction to this article has been published: Pal et al., J. Cell Biol. 175 (4) 671
Published 25 September 2006. doi:10.1083/jcb.200603152
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 7, 1047-1058
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Article

An antiangiogenic neurokinin-B/thromboxane A2 regulatory axis



Saumen Pal1, Jing Wu1, Justin K. Murray3, Samuel H. Gellman3, Michele A. Wozniak1, Patricia J. Keely1, Meghan E. Boyer1, Timothy M. Gomez2, Sean M. Hasso2, John F. Fallon2, and Emery H. Bresnick1

1 Department of Pharmacology and 2 Department of Anatomy, University of Wisconsin Medical School, Madison, WI 53706
3 Department of Chemistry, University of Wisconsin, Madison, Madison, WI 53706

Correspondence to Emery H. Bresnick: ehbresni{at}wisc.edu

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' 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.

Abbreviations used in this paper: CAM, chicken chorioallantoic membrane; FGFR1, FGF receptor 1; HAEC, human aortic endothelial cell, HMVEC, human microvascular endothelial cell; HUVEC, human umbilical vein endothelial cell; IBMX, 3-isobutyl-1-methylxanthine; NK-B, neurokinin B; mNK-B, mutant NK-B; SP, substance P; TXA2, thromboxane A2; VEGFR, VEGF receptor; YSEC, mouse yolk sac endothelial cell.


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