title: Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart.
abstract: 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 alpha4beta1 integrin on sympathetic neurons and vascular cell adhesion molecule-1 (VCAM-1) in the heart plays a role in cardiac innervation. The alpha4 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 alpha4 and beta1 integrin subunits. Intrathoracic injection of function-blocking antibodies to alpha4 and VCAM-1, as well as a small molecule inhibitor of alpha4 integrins, significantly reduced sympathetic innervation of the heart. These results indicate that the interaction between alpha4 integrin and VCAM-1 is important for sympathetic innervation of the heart.
authors.affiliation: Neuroscience Research Institute and Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Wingerd
authors.forename: Nichol L
authors.initials: NL
authors.lastname: Goodman
authors.forename: Jason W
authors.initials: JW
authors.lastname: Tresser
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Smail
authors.forename: Sergiu T
authors.initials: ST
authors.lastname: Leu
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Rohan
authors.forename: Jan L
authors.initials: JL
authors.lastname: Pring
authors.forename: David Y
authors.initials: DY
authors.lastname: Jackson
authors.forename: Dennis O
authors.initials: DO
authors.lastname: Clegg
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D002645:Chickens; D005728:Ganglia, Sympathetic / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D006321:Heart / Q000254:growth & development / Q000294:innervation*; D039441:Integrin alpha4 / Q000276:immunology / Q000502:physiology*; D039041:Integrin alpha4beta1 / Q000502:physiology; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D020318:Rats, Long-Evans; D011994:Recombinant Proteins / Q000494:pharmacology; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000906:Antibodies; D039041:Integrin alpha4beta1; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4