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The Journal of Neuroscience, December 15, 2002, 22(24):10772-10780

4 Integrins and Vascular Cell Adhesion Molecule-1 Play a Role in Sympathetic Innervation of the Heart

Kevin L. Wingerd¹, Nichol L. Goodman¹, Jason W. Tresser¹, Matthew M. Smail¹, Sergiu T. Leu¹, Steven J. Rohan¹, Jan L. Pring¹, David Y. Jackson², and Dennis O. Clegg¹

¹ Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106, and ² Genentech Inc., Department of Bioorganic Chemistry, South San Francisco, California 94080

Sympathetic neurons innervate the heart early in postnatal development, an event that is crucial for proper modulation of blood pressure and cardiac function. However, the axon guidance cues that direct sympathetic neurons to the heart, and the neuronal receptors that recognize those cues, are poorly understood. Here we present evidence that interactions between the 41 integrin on sympathetic neurons and vascular cell adhesion molecule-1 (VCAM-1) in the heart plays a role in cardiac innervation.

The 4 subunit was detected on postnatal rat superior cervical ganglion (SCG) neurons in culture and in cryosections of SCG and heart. VCAM-1 immunoreactivity was detected on cardiac myocytes that associate with invading sympathetic neurons. Purified recombinant soluble VCAM-1 (rsVCAM-1) stimulated SCG neurite outgrowth at levels comparable with laminin 2/4 and fibronectin (Fn), and outgrowth on rs-VCAM-1 and Fn was blocked by antibodies specific for the 4 and 1 integrin subunits. Intrathoracic injection of function-blocking antibodies to 4 and VCAM-1, as well as a small molecule inhibitor of 4 integrins, significantly reduced sympathetic innervation of the heart. These results indicate that the interaction between 4 integrin and VCAM-1 is important for sympathetic innervation of the heart.

Key words: integrins; vascular cell adhesion molecule-1; sympathetic neurons; heart; neurite outgrowth; neural development

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222410772-09$05.00/0

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