Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

PNAS 104 (11): 4647-4652

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / NEUROSCIENCE

VEGF is an essential mediator of the neurogenic and behavioral actions of antidepressants

Jennifer L. Warner-Schmidt Ronald S. Duman*

Departments of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, CT 06508

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved January 19, 2007

Received for publication November 20, 2006.

Abstract: The neural mechanisms underlying the cellular and behavioral responses to antidepressants are not yet known. Up-regulation of growth factors and adult neurogenesis suggest a role for one or more of these factors in the action of antidepressants. One candidate of interest is vascular endothelial growth factor (VEGF), which was initially characterized for its role in angiogenesis, but also exerts direct mitogenic effects on neural progenitors in vitro. Results of this study demonstrate that VEGF is induced by multiple classes of antidepressants at time points consistent with the induction of cell proliferation and therapeutic action of these treatments. We find that VEGF signaling through the Flk-1 receptor is required for antidepressant-induced cell proliferation. We also show that VEGF-Flk-1 signaling is required and sufficient for behavioral responses in two chronic and two subchronic antidepressant models. Taken together, these studies identify VEGF and VEGF-Flk-1 signaling as mediators of antidepressant actions and potential targets for therapeutic intervention.

Key Words: desipramine • electroconvulsive shock • endothelial cells • fluoxetine • neurogenesis


Author contributions: J.L.W.-S., and R.S.D. designed research; J.L.W.-S. performed research; J.L.W.-S. analyzed data; and J.L.W.-S. and R.S.D. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0610282104/DC1.

*To whom correspondence should be addressed at: 34 Park Street, New Haven, CT 06508. E-mail: ronald.duman{at}yale.edu

© 2007 by The National Academy of Sciences of the USA


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Neurotransmitter-mediated control of neurogenesis in the adult vertebrate brain.
D. A. Berg, L. Belnoue, H. Song, and A. Simon (2013)
Development 140, 2548-2561
   Abstract »    Full Text »    PDF »
Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder.
C.-T. Chiu, Z. Wang, J. G. Hunsberger, and D.-M. Chuang (2013)
Pharmacol. Rev. 65, 105-142
   Abstract »    Full Text »    PDF »
Examination of Org 26576, an AMPA receptor positive allosteric modulator, in patients diagnosed with major depressive disorder: an exploratory, randomized, double-blind, placebo-controlled trial.
K. R. Nations, P. Dogterom, R. Bursi, J. Schipper, S. Greenwald, D. Zraket, L. Gertsik, J. Johnstone, A. Lee, Y. Pande, et al. (2012)
J Psychopharmacol 26, 1525-1539
   Abstract »    Full Text »    PDF »
Vascular Endothelial Growth Factor-dependent Spinogenesis Underlies Antidepressant-like Effects of Enriched Environment.
Y.-F. Huang, C.-H. Yang, C.-C. Huang, and K.-S. Hsu (2012)
J. Biol. Chem. 287, 40938-40955
   Abstract »    Full Text »    PDF »
Systemic anti-vascular endothelial growth factor therapies induce a painful sensory neuropathy.
A. Verheyen, E. Peeraer, R. Nuydens, J. Dhondt, K. Poesen, I. Pintelon, A. Daniels, J.-P. Timmermans, T. Meert, P. Carmeliet, et al. (2012)
Brain 135, 2629-2641
   Abstract »    Full Text »    PDF »
Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress.
H. Son, M. Banasr, M. Choi, S. Y. Chae, P. Licznerski, B. Lee, B. Voleti, N. Li, A. Lepack, N. M. Fournier, et al. (2012)
PNAS 109, 11378-11383
   Abstract »    Full Text »    PDF »
Diverse roles for VEGF-A in the nervous system.
F. Mackenzie and C. Ruhrberg (2012)
Development 139, 1371-1380
   Abstract »    Full Text »    PDF »
Neurofibromin Modulates Adult Hippocampal Neurogenesis and Behavioral Effects of Antidepressants.
Y. Li, Y. Li, R. M. McKay, D. Riethmacher, and L. F. Parada (2012)
J. Neurosci. 32, 3529-3539
   Abstract »    Full Text »    PDF »
The mood stabilizer lamotrigine produces antidepressant behavioral effects in rats: role of brain-derived neurotrophic factor.
Nanxin Li, Xiaolu He, Xiaoli Qi, Yu Zhang, and Shuchang He (2010)
J Psychopharmacol 24, 1772-1778
   Abstract »    PDF »
Implications of the Functional Integration of Adult-Born Hippocampal Neurons in Anxiety-Depression Disorders.
D. J. David, J. Wang, B. A. Samuels, Q. Rainer, I. David, A. M. Gardier, and R. Hen (2010)
Neuroscientist 16, 578-591
   Abstract »    PDF »
{alpha}2-Adrenoceptor Blockade Accelerates the Neurogenic, Neurotrophic, and Behavioral Effects of Chronic Antidepressant Treatment.
S. U. Yanpallewar, K. Fernandes, S. V. Marathe, K. C. Vadodaria, D. Jhaveri, K. Rommelfanger, U. Ladiwala, S. Jha, V. Muthig, L. Hein, et al. (2010)
J. Neurosci. 30, 1096-1109
   Abstract »    Full Text »    PDF »
Induction of Neuronal Vascular Endothelial Growth Factor Expression by cAMP in the Dentate Gyrus of the Hippocampus Is Required for Antidepressant-Like Behaviors.
J.-S. Lee, D.-J. Jang, N. Lee, H.-G. Ko, H. Kim, Y.-S. Kim, B. Kim, J. Son, S. H. Kim, H. Chung, et al. (2009)
J. Neurosci. 29, 8493-8505
   Abstract »    Full Text »    PDF »
GABA-cAMP Response Element-Binding Protein Signaling Regulates Maturation and Survival of Newly Generated Neurons in the Adult Hippocampus.
R. Jagasia, K. Steib, E. Englberger, S. Herold, T. Faus-Kessler, M. Saxe, F. H. Gage, H. Song, and D. C. Lie (2009)
J. Neurosci. 29, 7966-7977
   Abstract »    Full Text »    PDF »
A New Role for FGF2 as an Endogenous Inhibitor of Anxiety.
J. A. Perez, S. M. Clinton, C. A. Turner, S. J. Watson, and H. Akil (2009)
J. Neurosci. 29, 6379-6387
   Abstract »    Full Text »    PDF »
Role and Therapeutic Potential of VEGF in the Nervous System.
C. Ruiz de Almodovar, D. Lambrechts, M. Mazzone, and P. Carmeliet (2009)
Physiol Rev 89, 607-648
   Abstract »    Full Text »    PDF »
Enhanced Adult Neurogenesis and Angiogenesis and Altered Affective Behaviors in Mice Overexpressing Vascular Endothelial Growth Factor 120.
H. Udo, Y. Yoshida, T. Kino, K. Ohnuki, W. Mizunoya, T. Mukuda, and H. Sugiyama (2008)
J. Neurosci. 28, 14522-14536
   Abstract »    Full Text »    PDF »
Electroconvulsive seizure and VEGF increase the proliferation of neural stem-like cells in rat hippocampus.
E. Segi-Nishida, J. L. Warner-Schmidt, and R. S. Duman (2008)
PNAS 105, 11352-11357
   Abstract »    Full Text »    PDF »
VEGF promotes vascular sympathetic innervation.
S. B. Marko and D. H. Damon (2008)
Am J Physiol Heart Circ Physiol 294, H2646-H2652
   Abstract »    Full Text »    PDF »
Chronic Fluoxetine Stimulates Maturation and Synaptic Plasticity of Adult-Born Hippocampal Granule Cells.
J.-W. Wang, D. J. David, J. E. Monckton, F. Battaglia, and R. Hen (2008)
J. Neurosci. 28, 1374-1384
   Abstract »    Full Text »    PDF »
cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response.
T. L. Gur, A. C. Conti, J. Holden, A. J. Bechtholt, T. E. Hill, I. Lucki, J. E. Malberg, and J. A. Blendy (2007)
J. Neurosci. 27, 7860-7868
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882