Abstract 306: Sympathetic Reinnervation is Required for Mammalian Cardiac Regeneration.

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Ian A White ◽  
Julie Gordon ◽  
Wayne Balkan ◽  
Joshua M Hare
Keyword(s):  
Sympathetic Innervation ◽  
Cardiac Regeneration ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Scar Tissue ◽  
Neonatal Mouse ◽  
Autonomic Nerves ◽  
Mouse Heart ◽  
Age Related ◽  
Innate Ability

Rationale: Established animal models of limb and tissue regeneration with re-vascularization demonstrate a critical dependence on concurrent reinnervation by the peripheral nervous system. Objective: Considering the significant abundance of autonomic nerves in the mammalian heart we tested the hypothesis that reinnervation is required for neonatal mouse cardiac regeneration. Methods and Results: Crossing Wnt1:cre transgenic mice with a double-tandem (td) tomato reporter strain identifies all neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. Whole mount epi-fluorescence microscopy facilitated the clear resolution of subepicardial autonomic nerves in the mouse ventricles providing unprecedented detail of the subepicardial neuroanatomy of the mouse heart. Sympathetic nerve bundles envelop the entire heart and extend to the tip of the ventricular apex. Our data demonstrate that during regeneration of the resected ventricular apex of the neonatal mouse heart, sympathetic nerves fibers undergo concurrent re-growth into the injury site resulting in complete sympathetic reinnervation of the regenerated tissue. Sympathectomy of the heart, induced by administration of 6-OHDA, was sufficient to block innate cardiac regeneration in the neonatal mouse. Conclusions: We report that the innate ability of the neonatal mouse heart to undergo regeneration in response to injury is dependent on sympathetic innervation of the ventricular myocardium. Ablation of post-ganglionic sympathetic nerves blocks the innate regenerative capacity of neonatal mouse hearts suggesting that sympathetic reinnervation is critical for ventricular regeneration. This finding has significant implications for adult regeneration following myocardial infarction where nerve growth is hindered by age related influences and scar tissue.

Abstract 17185: Sympathetic Reinnervation is Required for Mammalian Cardiac Regeneration

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Ian A White ◽  
Julie Gordon ◽  
Wayne Balkan ◽  
Joshua M Hare
Keyword(s):  
Sympathetic Innervation ◽  
Cardiac Regeneration ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Neonatal Mouse ◽  
Left Ventricular Myocardium ◽  
Autonomic Nerves ◽  
Mouse Heart ◽  
Minimal Scarring ◽  
Age Related

Rationale: Established animal models of tissue and limb regeneration demonstrate a critical dependence on concurrent reinnervation by the peripheral nervous system. The abundance of autonomic nerves in the mammalian heart suggests they play a similar role in the response to cardiac injury. Objective: To test the hypothesis that reinnervation is required for innate neonatal cardiac regeneration. Methods and Results: Crossing Wnt1:cre transgenic mice with a double-tandem (td) tomato reporter strain identified all neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. Whole mount epi-fluorescence microscopy facilitated the clear resolution of subepicardial autonomic nerves in the mouse ventricles providing unprecedented detail of the subepicardial neuroanatomy of the mouse heart. We confirmed that sympathetic nerve structures envelop the entire heart, and importantly, exhibit robust re-growth into the regenerating myocardium following resection of the left ventricular apex in neonatal mice. While innervated hearts regenerate with minimal scarring to the left ventricular myocardium, we report that innate cardiac regeneration was inhibited following sympathectomy, as determined by cross-sectional percentage of viable LV myocardium (n=9, 0.87±1.4% vs. n=6, 14.05±4.4% ; p<0.01). Conclusions: Ablation of post-ganglionic sympathetic nerves blocks the innate regenerative capacity of neonatal mouse hearts. Therefore, the innate ability of the neonatal mouse heart to undergo regeneration in response to injury is dependent on sympathetic innervation of the ventricular myocardium. This finding has significant implications for adult regeneration following myocardial infarction where nerve growth is hindered by age related influences and scar tissue.

scholarly journals Sympathetic Reinnervation Is Required for Mammalian Cardiac Regeneration

2015 ◽  
Vol 117 (12) ◽  
pp. 990-994 ◽  
Author(s):  
Ian A. White ◽  
Julie Gordon ◽  
Wayne Balkan ◽  
Joshua M. Hare
Keyword(s):  
Sympathetic Innervation ◽  
Cardiac Regeneration ◽  
Ventricular Myocardium ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Epifluorescence Microscopy ◽  
Left Ventricular Myocardium ◽  
Autonomic Nerves ◽  
Cross Sectional ◽  
Age Related

Rationale: Although mammalian cardiac regeneration can occur in the neonatal period, the factors involved in this process remain to be established. Because tissue and limb regeneration require concurrent reinnervation by the peripheral nervous system, we hypothesized that cardiac regeneration also requires reinnervation. Objective: To test the hypothesis that reinnervation is required for innate neonatal cardiac regeneration. Methods and Results: We crossed a Wnt1-Cre transgenic mouse with a double-tandem Tomato reporter strain to identify neural crest-derived cell lineages including the peripheral autonomic nerves in the heart. This approach facilitated the precise visualization of subepicardial autonomic nerves in the ventricles using whole mount epifluorescence microscopy. After resection of the left ventricular apex in 2-day-old neonatal mice, sympathetic nerve structures, which envelop the heart under normal conditions, exhibited robust regrowth into the regenerating myocardium. Chemical sympathectomy inhibited sympathetic regrowth and subsequent cardiac regeneration after apical resection significantly (scar size as cross-sectional percentage of viable left ventricular myocardium, n=9; 0.87%±1.4% versus n=6; 14.05±4.4%; P <0.01). Conclusions: These findings demonstrate that the profound regenerative capacity of the neonatal mammalian heart requires sympathetic innervation. As such, these data offer significant insights into an underlying basis for inadequate adult regeneration after myocardial infarction, a situation where nerve growth is hindered by age-related influences and scar tissue.

scholarly journals Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis

2017 ◽  
Vol 312 (3) ◽  
pp. H608-H621 ◽  
Author(s):  
Olujimi A. Ajijola ◽  
Robert L. Lux ◽  
Anadjeet Khahera ◽  
OhJin Kwon ◽  
Eric Aliotta ◽  
...  
Keyword(s):  
Conduction Velocity ◽  
Diffusion Tensor ◽  
Sympathetic Innervation ◽  
Stellate Ganglion ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Electrical Activation ◽  
Dependent Manner ◽  
Anterior Myocardial Infarction ◽  
Cardiac Sympathetic Innervation

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals ( P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis. NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/ .

scholarly journals Age-Related Variation in Sympathetic Nerve Distribution in the Human Spleen

2021 ◽  
Vol 15 ◽  
Author(s):  
Cindy G. J. Cleypool ◽  
David J. Brinkman ◽  
Claire Mackaaij ◽  
Peter G. J. Nikkels ◽  
Martijn A. Nolte ◽  
...  
Keyword(s):  
T Cells ◽  
Sympathetic Nerve ◽  
Close Association ◽  
Sympathetic Innervation ◽  
Sympathetic Nerves ◽  
Human Spleen ◽  
Related Variation ◽  
Age Related ◽  
Splenic Parenchyma ◽  
Anti Inflammatory

Introduction: The cholinergic anti-inflammatory pathway (CAIP) has been proposed as an efferent neural pathway dampening the systemic inflammatory response via the spleen. The CAIP activates the splenic neural plexus and a subsequent series of intrasplenic events, which at least require a close association between sympathetic nerves and T cells. Knowledge on this pathway has mostly been derived from rodent studies and only scarce information is available on the innervation of the human spleen. This study aimed to investigate the sympathetic innervation of different structures of the human spleen, the topographical association of nerves with T cells and age-related variations in nerve distribution.Materials and Methods: Spleen samples were retrieved from a diagnostic archive and were allocated to three age groups; neonates, 10–25 and 25–70 years of age. Sympathetic nerves and T cells were identified by immunohistochemistry for tyrosine hydroxylase (TH) and the membrane marker CD3, respectively. The overall presence of sympathetic nerves and T cells was semi-automatically quantified and expressed as total area percentage. A predefined scoring system was used to analyze the distribution of nerves within different splenic structures.Results: Sympathetic nerves were observed in all spleens and their number appeared to slightly increase from birth to adulthood and to decrease afterward. Irrespective to age, more than halve of the periarteriolar lymphatic sheaths (PALSs) contained sympathetic nerves in close association with T cells. Furthermore, discrete sympathetic nerves were observed in the capsule, trabeculae and red pulp and comparable to the total amount of sympathetic nerves, showed a tendency to decrease with age. No correlation was found between the number of T cells and sympathetic nerves.Conclusion: The presence of discrete sympathetic nerves in the splenic parenchyma, capsule and trabecular of human spleens could suggest a role in functions other than vasoregulation. In the PALS, sympathetic nerves were observed to be in proximity to T cells and is suggestive for the existence of the CAIP in humans. Since sympathetic nerve distribution shows interspecies and age-related variation, and our general understanding of the relative and spatial contribution of splenic innervation in immune regulation is incomplete, it remains difficult to estimate the anti-inflammatory potential of targeting splenic nerves in patients.

scholarly journals Ectopic atrial arrhythmias arising from canine thoracic veins during in vivo stellate ganglia stimulation

2008 ◽  
Vol 295 (2) ◽  
pp. H691-H698 ◽  
Author(s):  
Alex Y. Tan ◽  
Shengmei Zhou ◽  
Byung Chun Jung ◽  
Masahiro Ogawa ◽  
Lan S. Chen ◽  
...  
Keyword(s):  
Pulmonary Vein ◽  
Sinus Node ◽  
Periodic Acid ◽  
Sympathetic Innervation ◽  
Sympathetic Nerves ◽  
Atrial Arrhythmias ◽  
Periodic Acid Schiff ◽  
Stellate Ganglia ◽  
Ectopic Beats

The purpose of the present study was to determine whether thoracic veins may act as ectopic pacemakers and whether nodelike cells and rich sympathetic innervation are present at the ectopic sites. We used a 1,792-electrode mapping system with 1-mm resolution to map ectopic atrial arrhythmias in eight normal dogs during in vivo right and left stellate ganglia (SG) stimulation before and after sinus node crushing. SG stimulation triggered significant elevations of transcardiac norepinephrine levels, sinus tachycardia in all dogs, and atrial tachycardia in two of eight dogs. Sinus node crushing resulted in a slow junctional rhythm (51 ± 6 beats/min). Subsequent SG stimulation induced 20 episodes of ectopic beats in seven dogs and seven episodes of pulmonary vein tachycardia in three dogs (cycle length 273 ± 35 ms, duration 16 ± 4 s). The ectopic beats arose from the pulmonary vein ( n = 11), right atrium ( n = 5), left atrium ( n = 2), and the vein of Marshall ( n = 2). There was no difference in arrhythmogenic effects of left vs. right SG stimulation (13/29 vs. 16/29 episodes, P = nonsignificant). There was a greater density of periodic acid Schiff-positive cells ( P < 0.05) and sympathetic nerves ( P < 0.05) at the ectopic sites compared with other nonectopic atrial sites. We conclude that, in the absence of a sinus node, thoracic veins may function as subsidiary pacemakers under heightened sympathetic tone, becoming the dominant sites of initiation of focal atrial arrhythmias that arise from sites with abundant sympathetic nerves and periodic acid Schiff-positive cells.

scholarly journals Cellular Senescence in Lung Fibrosis

2021 ◽  
Vol 22 (13) ◽  
pp. 7012
Author(s):  
Fernanda Hernandez-Gonzalez ◽  
Rosa Faner ◽  
Mauricio Rojas ◽  
Alvar Agustí ◽  
Manuel Serrano ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cellular Senescence ◽  
Lung Fibrosis ◽  
Lung Diseases ◽  
Physiological Mechanism ◽  
Lung Parenchyma ◽  
Scar Tissue ◽  
Interstitial Lung Diseases ◽  
Cellular Damage ◽  
Age Related

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

2014 ◽  
Vol 112 (11) ◽  
pp. 951-959 ◽  
Author(s):  
Morten Eriksen ◽  
Arnfinn Ilebekk ◽  
Alessandro Cataliotti ◽  
Cathrine Rein Carlson ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker

SummaryBradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

Peptidomics Analysis of Transient Regeneration in the Neonatal Mouse Heart

2017 ◽  
Vol 118 (9) ◽  
pp. 2828-2840 ◽  
Author(s):  
Yi Fan ◽  
Qijun Zhang ◽  
Hua Li ◽  
Zijie Cheng ◽  
Xing Li ◽  
...  
Keyword(s):  
Neonatal Mouse ◽  
Mouse Heart

scholarly journals Acute inflammation stimulates a regenerative response in the neonatal mouse heart

Cell Research ◽  
2015 ◽  
Vol 25 (10) ◽  
pp. 1137-1151 ◽  
Author(s):  
Chunyong Han ◽  
Yu Nie ◽  
Hong Lian ◽  
Rui Liu ◽  
Feng He ◽  
...  
Keyword(s):  
Acute Inflammation ◽  
Neonatal Mouse ◽  
Mouse Heart ◽  
Regenerative Response
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