Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor

Christina U. Lorentz, Eric N. Alston, Todd Belcik, Jonathan Lindner, George Giraud, Beth Habecker

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33 Citations (Scopus)

Abstract

Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75 NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR-/-) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR-/- ventricles and discovered that the subendocardium of the p75NTR-/- left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/dt, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Nerve Growth Factor Receptor
Adrenergic Receptors
Semaphorin-3A
Nerve Growth Factor
Neurons
Heart Ventricles
Axons
Norepinephrine
trkA Receptor
Adrenergic Fibers
Tyrosine 3-Monooxygenase
Denervation
Nerve Fibers
mouse TNFRSF16 protein
Cardiac Arrhythmias
Phenotype

Keywords

  • Nerve growth factor
  • Semaphorin 3a
  • Sympathetic innervation
  • Ventricular arrhythmias

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor",
abstract = "Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75 NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR-/-) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR-/- ventricles and discovered that the subendocardium of the p75NTR-/- left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/dt, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.",
keywords = "Nerve growth factor, Semaphorin 3a, Sympathetic innervation, Ventricular arrhythmias",
author = "Lorentz, {Christina U.} and Alston, {Eric N.} and Todd Belcik and Jonathan Lindner and George Giraud and Beth Habecker",
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doi = "10.1152/ajpheart.01128.2009",
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T1 - Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor

AU - Lorentz, Christina U.

AU - Alston, Eric N.

AU - Belcik, Todd

AU - Lindner, Jonathan

AU - Giraud, George

AU - Habecker, Beth

PY - 2010/6

Y1 - 2010/6

N2 - Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75 NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR-/-) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR-/- ventricles and discovered that the subendocardium of the p75NTR-/- left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/dt, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

AB - Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75 NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR-/-) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR-/- ventricles and discovered that the subendocardium of the p75NTR-/- left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/dt, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.

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KW - Ventricular arrhythmias

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