| Sympathetic neurons innervate the heart early in postnatal development, an event which 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.; Sympathetic nerves are known to express several integrins. Coincidently many integrin binding ECM proteins are present in the developing and adult heart. It is very likely that integrins are used by sympathetic nerve axons to extend and maintain neurites within the heart.; I have shown that the alpha4beta1 integrin and its putative ligand vascular cell adhesion molecule-1 (VCAM-1) play an important role during sympathetic innervation of the heart. Both alpha4 integrins and VCAM-1 are in the right places at the right times for these two proteins to be interacting. Furthermore, alpha4 integrin is not only expressed by sympathetic neurons, it is also functionally active in in vitro neurite outgrowth assays. Upon closer examination of the alpha4 integrin I was able to observe several developmentally regulated changes occurring with respect to localization, function, and molecular weight of the protein.; Using both function blocking antibodies and a small peptide inhibitor I was able to perturb alpha4 integrin and VCAM-1 function during the first postnatal week of the rat. This resulted in a 30% reduction in the number of fibers within the ventricles and an equal amount of reduction of norepinephrine.; The regulation of alpha4beta1 function, and localization of alpha4 and VCAM-1, are consistent with a role for the alpha4beta1-VCAM-1 interaction in extension of sympathetic axons into the myocardium. The blockade of alpha4 and VCAM-1 function are also consistent with both of these proteins being involved with both the establishment and maintenance of the sympathetic innervation of the heart. |
