Overexpression of NGF within the Heart of Transgenic Mice Causes Hyperinnervation, Cardiac Enlargement, and Hyperplasia of Ectopic Cells

Abstract

Nerve growth factor (NGF) supports the survival of developing sympathetic and a subpopulation of sensory neurons. In the adult it participates in maintenance of the neurotransmitter phenotype of responsive neurons. The amount of NGF synthesized by a given target tissue determines its final innervation density; those developing neurons that fail to receive sufficient NGF undergo apoptosis. In order to examine the ramifications of this principle in the context of a specific target organ, a transgenic mouse model was developed in which NGF expression was increased in developing and adult cardiac tissue by placing a NGF minigene under the transcriptional control of the cardiac-specific alpha-myosin heavy chain promoter. Transgenic mice developed cardiac enlargement secondary to both an increase in myocardial mass and the presence of an abundant ectopic cell population. Immunohistochemical analyses with the neural marker S-100 revealed staining of a subpopulation of ectopic cells, suggesting their derivation from the neural crest. Whereas immunostaining for the neuronal-specific protein neuron-specific enolase demonstrated labeling of another subpopulation of ectopic cells within the heart. Measurements of cardiac tissue catecholamine levels revealed a marked elevation in transgenic mice, consistent with sympathetic hyperinnervation. Analysis of mediastinal sympathetic ganglia revealed increases in both the size and the number of neurons. In this model, increased expression of NGF produced hyperinnervation of the heart, pathological cardiac growth, and the recruitment and/or expansion of an ectopic, neural crest-derived cell type.

Coronary veins determine the pattern of sympathetic innervation in the developing heart

“…For example, ARTN expression in VSMCs shifts from central to peripheral blood vessels in parallel with sympathetic axon extension along these vessels (Honma et al, 2002). In the developing heart, NGF is important for sympathetic innervation of the myocardium (Hassankhani et al, 1995;Ieda et al, 2004). In Ngf −/− ; Bax −/− embryos, there appears to be normal sympathetic axon extension along the extracardiac vasculature but a drastic decrease in sympathetic innervation of the heart .…”

Injection of Nerve Growth Factor Into Stellate Ganglia Improves Norepinephrine Reuptake Into Failing Hearts

“…Transgenic mice overexpressing NGF in the heart show elevated cardiac catecholamine levels and sympathetic hyperinnervation. 23, 24 Cao et al 25 reported that a prolonged (5 weeks) infusion of NGF into the left stellate ganglion of dogs after myocardial infarction induces hyperinnervation, which results in ventricular tachyarrythmias and sudden cardiac death. However, in vivo, nerve sprouting was not observed as early as 1 week after the beginning of NGF application.…”

“…2 Therefore, a doubled NE reuptake in the latter study is rather caused by the previously reported cardiac hyperinnervation in these mice. 24 How does NGF improve NET function? We did not observe a change of NET mRNA levels.…”

Age-related regional differences in cardiac nerve growth factor expression

“…Nerve growth factor (NGF) is the main neurotrophic factor that crucially controls the sympathetic tone of the mammalian heart (Levi-Montalcini 1976;Snider 1994;Hassankhani et al 1995). In parallel, NGF has been identified as a pro-survival factor for cardiomyocytes by developing anti-apoptotic effects via tyrosine kinase A (TrkA) receptor downstream signaling (Caporali et al 2008).…”