Overexpression of nerve growth factor in the hearts of transgenic mice: Neural and cardiac consequences

Abstract

Neurotrophins are an important class of structurally related proteins which play roles in both the developing and mature nervous system. Nerve growth factor (NGF), the prototypic member of the neutrophin family, was discovered more than forty years ago and characterized as a target-derived survival factor for the developing sympathetic and sensory neurons. The "neutrophin hypothesis" proposed that the limited supply of this factor determined the final innervation density of individual target organs. To examine the ramifications of this hypothesis, in the context of the specific target tissue, we generated transgenic mice which over-express NGF exclusively in developing and adult cardiac tissue. This study focuses on the analysis of histological, physiological and biochemical features of the cardiovascular and peripheral nervous system of these mice. NGF over-expression in transgenic myocardium, beginning on or before embryonic day 12, led to an increased number of sympathetic neurons within mediastinal and other sympathetic ganglia, suggesting a reduction in naturally occurring neuronal cell death. Catecholamine levels were elevated many fold in postnatal cardiac tissue, consistent with hyperinnervation by noradrenergic fibers. Moreover, neonatal catecholamine levels were equivalent to adult levels, indicating an accelerated rate of acquisition of a noradrenergic phenotype. Sympathetic hyperinnervation and catecholamine excess resulted in myocyte damage, sarcomeric disorganization and necrosis, as evident by histological and ultrastructural analyses. Hemodynamic measurements performed in 4-month old transgenic mice revealed cardiac dysfunction, with abnormalities in both systolic and diastolic components. Finally, the transgenic cardiac base (i.e. the atria and atrial appendages) contained at least two ectopic cell populations. Immunohistochemical analysis of these cells suggested that they were derived from the neural crest lineage. Overall, our data reinforce the neurotrophin hypothesis and suggest that premature and excessive NGF synthesis, within the heart, profoundly alters cardiac development and results in cardiac dysfunction.