Role Of Sympathetic Innervation Research Articles

The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures.

Neonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI-induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2 -adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex-specific role in mediating neonatal muscle growth, as the cross-sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β-adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β-adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.

Somatosensory innervation of adipose tissues

The increasing prevalence of obesity and type 2 diabetes has led to a greater interest in adipose tissue physiology. Adipose tissue is now understood as an organ with endocrine and thermogenic capacities in addition to its role in fat storage. It plays a critical role in systemic metabolism and energy regulation, and its activity is tightly regulated by the nervous system. Fat is now recognized to receive sympathetic innervation, which transmits information from the brain, as well as sensory innervation, which sends information into the brain. The role of sympathetic innervation in adipose tissue has been extensively studied. However, the extent and the functional significance of sensory innervation have long been unclear. Recent studies have started to reveal that sensory neurons robustly innervate adipose tissue and play an important role in regulating fat activity. This brief review will discuss both historical evidence and recent advances, as well as important remaining questions about the sensory innervation of adipose tissue.

Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia-Reperfusion: Roles of Sympathetic Innervation and Sex Differences.

Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 μg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post-I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (-4.2±7.9 versus -68.2±3.8 Δ%) compared with vehicle-treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad-lib fed or pair-fed saline-treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD+/NADH content (≈10-fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.

Stromal cell-derived NGF controls sympathetic innervation in subcutaneous fat

Stromal cell-derived NGF controls sympathetic innervation in subcutaneous fat

Defining a Role for G-Protein Coupled Receptor/cAMP/CRE-Binding Protein Signaling in Hair Follicle Stem Cell Activation

Manipulation of adrenergic signaling has been shown experimentally and clinically to affect hair follicle growth. In this study, we provide direct evidence that canonical cAMP/CRE-binding protein signaling through adrenergic receptors can regulate hair follicle stem cell (HFSC) activation and hair cycle. We found that CRE-binding protein activation is regulated through the hair cycle and coincides with HFSC activation. Both isoproterenol and procaterol, agonists of adrenergic receptors, show the capacity to activate the hair cycle in mice. Furthermore, deletion of ADRB2 receptor, which is thought to mediate sympathetic nervous system regulation of HFSCs, was sufficient to block HFSC activation. Downstream, stimulation of adenylyl cyclase with forskolin or inhibition of phosphodiesterase to increase cAMP accumulation or direct application of cAMP was each sufficient to promote HFSC activation and accelerate initiation of hair cycle. Genetic induction of a Designer Receptors Exclusively Activated by Designer Drug allele showed that G-protein coupled receptor/GαS stimulation, specifically in HFSCs, promoted the activation of the hair cycle. Finally, we provide evidence that G-protein coupled receptor/CRE-binding protein signaling can potentially act on HFSCs by promoting glycolytic metabolism, which was previously shown to stimulate HFSC activation. Together, these data provide mechanistic insights into the role of sympathetic innervation on HFSC function.

Abstract 15228: Role of Sympathetic Innervation in the Pathogenesis of Abdominal Aortic Aneurysm

Introduction: The objective of this study is to understand the role of neurological factors, specifically those from the perivascular sympathetic nervous system (SNS), on the initiation and development of Abdominal Aortic Aneurysm (AAA). Hypothesis: We hypothesize that the formation of AAA is associated with the loss of perivascular SNS-induced vasoconstriction specific to the aneurysm region. Methods: We developed a rat Abdominal Aortic Denervation (AAD) model, where the infrarenal aorta of Spauge Dawley rats was denervated with surgical removal of nerve fibers and chemical denervation with 10% phenol ( Figure. A ). A sham control group was included where the infrarenal aorta was treated with PBS. The arteries were harvested at 1 month after the surgeries for histological assessment. Results: The denervated aortas exhibited significant thinning of the aortic wall including the media and the adventitia, compared to the sham controls ( Figure. B ). Moreover, degradation of elastin, demonstrated by the fragmentation of elastic fibers and the decreased number of lamellar units, was also observed in the dennervated aortas in comparison to the sham controls. While the control aortas were well innervated with perivascular nerve bundles adjacent to the adventitia, no nerves were found surrounding the denervated aortas, suggesting successful denervation. Conclusions: We generated an AAD model that could be used for mechanistic understanding and therapeutic development of AAA. The preliminary data suggest a direct link between the lack of aortic sympathetic innervation and AAA formation. Long-term studies are currently underway to further characterize changes in the aortic walls after sympathetic denervation. Figure. (A) Illustration of the denervated region on the rat infrarenal aorta. ( B ) Histological staining of control and denervated rat abdominal aortas at 1 month after surgery. Yellow stars: para-aortic nerve bundles. Scale bar = 200 μm.

MON-032 Excessive Ovarian Sympathetic Activity Impairs Embryonic Development and Causes Reproductive and Metabolic Dysfunction

Nerve growth factor is a member of the neurotrophin family and within the ovary, it plays an important role in sympathetic innervation and in the development and maintenance of folliculogenesis. Despite its critical role, excessive levels of ovarian NGF may lead to ovarian pathology and to the development of features of polycystic ovary syndrome (PCOS), which is the most common endocrine disorder among women of reproductive age. Here, using a transgenic mouse model overexpressing NGF selectively in the ovary (17NF mice), we studied how ovarian sympathetic hyperactivity affects embryonic development and reproductive and metabolic function in adulthood. Firstly, we showed that ovarian NGF excess caused growth restriction in the developing female fetuses, which was driven by defects in the placenta function. Moreover, the 17NF fetuses experienced a reduction of germ cell number along with delayed gonocyte and primary oocyte maturation. The adult 17NF mice displayed irregular cyclicity and aberrant ovarian expression of steroidogenic genes and epigenetic markers. The ovarian sympathetic hyperactivity also led to increased systemic sympathetic outflow, indicated by increased circulating dopamine levels, and to metabolic dysfunction in adulthood. The 17NF mice had increased adiposity, impaired glucose metabolism and decreased energy expenditure. The subcutaneous and parametrial fat depots displayed impaired function due to ovarian NGF excess, wherein the subcutaneous fat increased mass by enhanced preadipocyte differentiation and enlarged adipocyte size, while the parametrial fat had smaller adipocyte size and a modest increase in stimulated lipolysis. These defects also led to hepatic steatosis. Overall, our findings indicate that ovarian sympathetic hyperactivity has deleterious effects on whole-body homeostasis and leads to impaired embryonic development and to reproductive and metabolic defects in adult life.

Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions.

The sympathetic nervous system (SNS) activates cAMP signaling and promotes trophic effects on brown adipose tissue (BAT) through poorly understood mechanisms. Because norepinephrine has been found to induce antiproteolytic effects on muscle and heart, we hypothesized that the SNS could inhibit autophagy in interscapular BAT (IBAT). Here, we describe that selective sympathetic denervation of rat IBAT kept at 25°C induced atrophy, and in parallel dephosphorylated forkhead box class O (FoxO), and increased cathepsin activity, autophagic flux, autophagosome formation, and expression of autophagy-related genes. Conversely, cold stimulus (4°C) for up to 72 h induced thermogenesis and IBAT hypertrophy, an anabolic effect that was associated with inhibition of cathepsin activity, autophagic flux, and autophagosome formation. These effects were abrogated by sympathetic denervation, which also upregulated Gabarapl1 mRNA. In addition, the cold-driven sympathetic activation stimulated the mechanistic target of rapamycin (mTOR) pathway, leading to the enhancement of protein synthesis, evaluated in vivo by puromycin incorporation, and to the inhibitory phosphorylation of Unc51-like kinase-1, a key protein in the initiation of autophagy. This coincided with a higher content of exchange protein-1 directly activated by cAMP (Epac1), a cAMP effector, and phosphorylation of Akt at Thr308, all these effects being abolished by denervation. Systemic treatment with norepinephrine for 72 h mimicked most of the cold effects on IBAT. These data suggest that the noradrenergic sympathetic inputs to IBAT restrain basal autophagy via suppression of FoxO and, in the setting of cold, stimulate protein synthesis via the Epac/Akt/mTOR-dependent pathway and suppress the autophagosome formation, probably through posttranscriptional mechanisms.NEW & NOTEWORTHY The underlying mechanisms related to the anabolic role of sympathetic innervation on brown adipose tissue (BAT) are unclear. We show that sympathetic denervation activates autophagic-lysosomal degradation, leading to a loss of mitochondrial proteins and BAT atrophy. Conversely, cold-driven sympathetic activation suppresses autophagy and stimulates protein synthesis, leading to BAT hypertrophy. Given its high-potential capacity for heat production, understanding the mechanisms that contribute to BAT mass is important to optimize chances of survival for endotherms in cold ambients.

2487-PUB: Purinergic Regulation of Adiponectin Exocytosis and the Role of Sympathetic Innervation for Adiponectin Secretion

The white adipocyte hormone adiponectin improves insulin sensitivity and has a protective role in the development of type 2 diabetes. The rapid incidence of obesity-associated disorders emphasizes the importance of understanding the regulation of adiponectin secretion. Hormones are typically secreted via regulated exocytosis but the mechanisms controlling adiponectin release remains inadequately investigated. We have previously demonstrated that catecholamines/cAMP trigger adiponectin exocytosis via activation of adrenergic beta-3-receptors (β3ARs) and Epac1, while elevations of intracellular Ca2+ potentiate the exocytotic process. White adipose tissue is highly innervated by sympathetic nerves, co-releasing norepinephrine (NE) and ATP, thus suggesting a role of the sympathetic nervous system in regulation of adiponectin secretion. Here we have studied the role of sympathetic innervation and purinergic signaling in adiponectin release. Extracellular NE triggered adipocyte exocytosis, whereas extracellular ATP potentiated NE-triggered adipocyte exocytosis. Short-term adiponectin secretion was stimulated by NE while ATP augmented the catecholamine-stimulated release. The effect of ATP was abolished in adipocytes pre-treated with a P2Y2-receptor antagonist. In adipocytes isolated from obese/diabetic mice, ATP-induced adiponectin release was abrogated together with a reduced gene expression of the P2Y2-receptor. Moreover, white adipose tissue content of NE and tyrosine hydroxylase was reduced in obese/diabetic mice. We propose that the physiological stimulatory pathway for adiponectin exocytosis is via sympathetic innervation, co-releasing NE and ATP which activates β3ARs (elevates cAMP) and P2Y2Rs (increases Ca2+). We also suggest that decreased NE and ATP release within the adipose tissue together with disrupted adipocyte purinergic signaling results in disturbed adiponectin release in diabetic/obese conditions. Disclosure S. Musovic: None. A.M. Komai: None. P. Micallef: None. Y. Wu: None. I. Wernstedt Asterholm: None. C.S. Olofsson: None.

Neonatal testosterone exposure induces early development of follicular cysts followed by sympathetic ovarian hyperinnervation.

This study analysed the temporal association between ovarian cyst development induced by neonatal androgenisation and sympathetic innervation. Neonatal rats (postnatal Days 1 to 5) were treated with testosterone or dihydrotestosterone and the effects were evaluated at postnatal Days 20, 40, 90 or 180. Ovulation rate, number of cystic follicles and density of sympathetic fibres were analysed. The effects of surgical denervation or gonadotrophin stimulation were also assessed. Rats exposed to testosterone showed no oestrous cycle activity and did not ovulate, maintaining a polycystic ovarian morphology at all ages studied. Also, a significant increase in ovarian density of noradrenergic fibres was detected at postnatal Days 90 and 180. Sympathectomy was unable to re-establish ovarian activity; however, human chorionic gonadotrophin stimulation was enough to induce ovulation. The impact of dihydrotestosterone on ovarian function was less noticeable, showing the coexistence of corpora lutea and cystic structures without changes in sympathetic innervation. Our findings suggest that a remodelling of ovarian sympathetic innervation occurs as a response to modifications in the pattern of follicular growth induced by testosterone. A role of sympathetic innervation in the maintenance of the polycystic condition is suggested.

Role of sympathetic innervation on cerebral artery remodeling during chronic hypoxia in fetal lambs (853.3)

Cerebral arteries adapt to chronic hypoxia by altering the phenotypes of the plastic and heterogeneous population of cells in the artery wall. Perivascular nerves also undergo differentiation during hypoxia and alter vasotrophic effects on arteries. Here we test the hypothesis that nerves from the superior cervical ganglia (SCG) mediate hypoxic remodeling of ovine cerebral arteries. Using a chronic hypoxia (CH) and unilateral sympathectomy (SANX) model, we tested effects of CH and SANX on tone, contractile proteins and cell proliferation. Contractile responses to electrical nerve stimulation were upregulated (794%) by CH. CH ↑ dopa beta hydroxylase by 360% and SANX ablated this. CH↓ colocalization of a synthetic isoform of myosin heavy chain (SMemb) with smooth muscle alpha actin (AA) by 69%. SANX ↑ the colocalization by 600% in hypoxic arteries. NE in culture ↓ the colocalization by 91% and co‐culture of NE with prazosin ↑ it by 1363%. Also CH ↓ area per cell by 9% (media) and 45% (adventitia) whereas SANX ↑ it by 42% and 89% respectively. Also, CH ↓ colocalization of Ki67 (marker for cell proliferation) with AA by 15% (media) and 69% (adventitia). Together, these results suggest that the sympathetic cerebrovascular innervation helps mediate hypoxic remodeling through potentiation of NE synthesis, increased stimulation of α‐1 adrenoceptors, and transformation toward a contractile smooth muscle phenotype.Grant Funding Source: Supported by NIH Grants HD‐31266 and NS‐076945

Effect of chronic cervical ganglionectomy on the spontaneous variability of internal carotid blood flow in the conscious rat

The role of sympathetic innervation in the control of spontaneous fluctuations of cerebral blood flow is still poorly understood. In conscious, unrestrained rats, blood flow velocity (pulsed Doppler) was measured in both internal carotid arteries 1 week after either excision of the right superior cervical ganglion (n = 8) or sham surgery (n = 6). Using Fourier-based techniques, spectral power of each carotid blood flow (CBF) was computed over the whole recording period (246 min), which was segmented into nine consecutive 27.3 min periods. Variability of CBF (spectral power) was ∼40% higher (P < 0.02) on the denervated than on the intact side at frequencies <1 Hz. Coherence between left and right CBFs was similar in the two groups of rats, except in the 0.01-0.1 Hz frequency range where it was lower (P < 0.05) in rats with unilateral sympathectomy (0.54 ± 0.03) than in intact rats (0.74 ± 0.06). In this frequency range, mathematically removing the influence of arterial pressure had little effect on coherence between CBFs in both groups of rats, so that coherence remained significantly lower in rats with unilateral sympathectomy (0.52 ± 0.03) than in intact rats (0.70 ± 0.06). This study indicates that sympathetic innervation has an overall buffering influence on CBF variability. This modulatory role is especially important in a frequency range corresponding to slow fluctuations of CBF (lasting from 10 to 100 s), which are essentially unrelated to fluctuations of arterial pressure.

Cardiac autonomic function in acutely nitric oxide deficient hypertensive rats: role of the sympathetic nervous system and oxidative stress

We evaluated the role of the sympathetic nervous system and oxidative stress in hemodynamic and autonomic control after acute inhibition of the synthesis of nitric oxide, using intravenous (i.v.) injection of 30mg·kg(-1) N(G)-nitro-l-arginine methyl ester (L-NAME) in adult Wistar rats. Baroreflex sensitivity (BRS) and heart rate variability (HRV) were measured as indices of cardiac autonomic control, before and after L-NAME treatment in rats with intact autonomic innervation, and in rats with chemical sympathectomy by 6-hydroxydopamine. Serum malondialdehyde (MDA) was measured as a marker of oxidative stress. In control rats, L-NAME treatment resulted in a significant rise in blood pressure, augmentation of BRS, and enhanced serum MDA. HRV showed an attenuation of total spectral power and high frequency spectral power, along with a rise of the low to high frequency ratio (LF:HF). Administration of L-NAME produced a pressor response even in sympathectomised rats, but augmented BRS was not observed, and the high frequency spectral power showed an increase, in addition to a significant decline of LF:HF and serum MDA. We therefore conclude that even though pressor response was unaffected, reversal of cardiac autonomic responses and decline in oxidative stress following sympathectomy in L-NAME-treated rats reflects a significant role for sympathetic innervation in acute L-NAME-induced hypertension.

Egr3 Dependent Sympathetic Target Tissue Innervation in the Absence of Neuron Death

Nerve Growth Factor (NGF) is a target tissue derived neurotrophin required for normal sympathetic neuron survival and target tissue innervation. NGF signaling regulates gene expression in sympathetic neurons, which in turn mediates critical aspects of neuron survival, axon extension and terminal axon branching during sympathetic nervous system (SNS) development. Egr3 is a transcription factor regulated by NGF signaling in sympathetic neurons that is essential for normal SNS development. Germline Egr3-deficient mice have physiologic dysautonomia characterized by apoptotic sympathetic neuron death and abnormal innervation to many target tissues. The extent to which sympathetic innervation abnormalities in the absence of Egr3 is caused by altered innervation or by neuron death during development is unknown. Using Bax-deficient mice to abrogate apoptotic sympathetic neuron death in vivo, we show that Egr3 has an essential role in target tissue innervation in the absence of neuron death. Sympathetic target tissue innervation is abnormal in many target tissues in the absence of neuron death, and like NGF, Egr3 also appears to effect target tissue innervation heterogeneously. In some tissues, such as heart, spleen, bowel, kidney, pineal gland and the eye, Egr3 is essential for normal innervation, whereas in other tissues such as lung, stomach, pancreas and liver, Egr3 appears to have little role in innervation. Moreover, in salivary glands and heart, two tissues where Egr3 has an essential role in sympathetic innervation, NGF and NT-3 are expressed normally in the absence of Egr3 indicating that abnormal target tissue innervation is not due to deregulation of these neurotrophins in target tissues. Taken together, these results clearly demonstrate a role for Egr3 in mediating sympathetic target tissue innervation that is independent of neuron survival or neurotrophin deregulation.

The influence of autonomic interventions on the sleep-wake-related changes in gastric myoelectrical activity in rats

Significant changes in autonomic activity occur at sleep-wake transitions and constitute an ideal setting for investigating the modulatory role of the autonomic nervous system on gastric myoelectrical activity (GMA). Using continuous power spectral analysis of electroencephalogram, electromyogram, and electrogastromyogram (EGMG) data from freely moving rats that had undergone chemical sympathetomy and/or truncal vagotomy, sleep-wake-related fluctuations in GMA were compared among the intervention groups. The pattern and extent of fluctuations in EGMG power across the sleep-wake states was blunted most significantly in rats undergoing both chemical sympathectomy and truncal vagotomy. The effect of these interventions also varied with respect to the transition between different sleep-wake states. The most prominent influences were observed between active waking and quiet sleep and between paradoxical sleep and quiet sleep. The sleep-wake-related fluctuations in EGMG power are a result of joint contributions from both sympathetic and vagal innervation. Vagotomy mainly resulted in a reduction in EGMG power, while the role of sympathetic innervation was unveiled by vagotomy and this was reflected most obviously in the extent of the fluctuations in EGMG power.

The role of sympathetic innervation in the developing rat gubernaculum

Background Testicular descent occurs in several steps, but the mechanism remains unknown. Recently, sympathetic nerves have been proposed to have a role. This study aimed to see if adrenergic agonists and antagonists affected the neonatal rat gubernacular cremaster sac in organ culture. Methods Cremaster sacs were collected from 2-day-old Sprague-Dawley male rats (n = 90) and placed in organ culture with/without (1) calcium chloride (0.45-1.8 mmol/L), (2) rat calcitonin gene-related peptide (CGRP) (714 nmol/L), (3) nifedipine (0.1-100 nmol/L), (4) isopreneline (10 μmol/L), and (5) guanethidine (10 μmol/L). Gubernacula were observed over 2 days for rhythmic peristalsis (>120 beats per minute for >1 minute). Results Addition of CGRP stimulated rhythmic contractility but only in the presence of calcium, with a dose-response to the level of calcium ions. Contractions induced by CGRP with calcium could be obliterated in a dose-response by nifedipine. Isoprenaline caused some increase in contractions with calcium but less than that seen with CGRP. No augmentation of effect was seen with CGRP and isopreneline together, and the level of contractility was the same with guanethidine. Conclusions Calcitonin gene-related peptide is the main effector for contractility of the rat cremaster sac, as long as calcium ions are present. Adrenergic agonists and antagonists had limited effects. Contractility could be inhibited with nifedipine, consistent with CGRP acting via a calcium-dependent pathway.

Involvement of α4 integrins in maintenance of cardiac sympathetic axons

Sympathetic neurons extend and maintain axons that innervate the myocardium, and proper innervation is important for cardiac function. However, the molecular basis for axon outgrowth and maintenance is not well understood. We have shown previously that the integrin α4β1 is expressed on developing axons, and the α4 function is important for the development of innervation in vivo [Wingerd, K.L., Goodman, N.L., Tresser, J.W., Smail, M.M., Leu, S.T., Rohan, S.J., Pring, J.L., Jackson, D.Y., and Clegg, D.O., 2002. Alpha 4 integrins and vascular cell adhesion molecule-1 play a role in sympathetic innervation of the heart. J. Neurosci. 22,10772–10780]. Here we examine the function of α4β1 integrins in the maintenance of cardiac sympathetic innervation in vitro and in vivo, and investigate integrin expression and function after myocardial infarction and in hypertensive rats. On substrates of vascular cell adhesion molecule-1 (VCAM-1), α4β1 was required for both initial outgrowth and maintenance of neurites in vitro. On fibronectin substrates, initial outgrowth requires only α4 integrins, but maintenance requires both α4 integrins and RGD-dependent integrins. In vivo, in adult Long Evans rats, inhibition of α4 integrins resulted in decreased maintenance of sympathetic fibers innervating the apex of the heart. However, α4 integrins were not detected on most sympathetic axons that sprout after myocardial infarction, and α4 function was not required for sprouting. Spontaneously hypertensive rats (SHR) have increased numbers of cardiac sympathetic fibers compared to the parental Wistar strain, but many of these lack α4 expression, and α4 function is not required for maintenance of these fibers in the heart. These results suggest that developing sympathetic axons and sprouting sympathetic axons use different mechanisms of outgrowth, and that maintenance of cardiac sympathetic innervation involves α4 integrins in some rat strains.

Sympathetic nervous system activity in rat thyroid: potential role in goitrogenesis

The role of sympathetic innervation in regulation of thyroid function is incompletely understood. We, therefore, carried out studies in rats utilizing techniques of norepinephrine turnover to assess thyroid sympathetic activity in vivo. Thyroidal sympathetic activity was increased 95% by exposure to cold (4 degrees C), 42% by chronic ingestion of an iodine-deficient diet, and 32% in rats fed a goitrogenic diet (low-iodine diet supplemented with propylthiouracil). In addition, fasting for 2 days reduced sympathetic nervous system activity in thyroid by 38%. Thyroid growth and 125I uptake were also compared in intact and decentralized hemithyroids obtained from animals subjected to unilateral superior cervical ganglion decentralization. Unilateral superior cervical ganglion decentralization led to a reduction in thyroid weight, in 125I uptake by thyroid tissue, and in TSH-induced stimulation of 125I uptake in decentralized hemithyroids. These results suggest that sympathetic activity in thyroid contributes to gland enlargement and may modulate tissue responsiveness to TSH.

Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression.

The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulators of NGF in cardiomyocytes, we found that endothelin-1 specifically upregulated NGF expression in primary cultured cardiomyocytes. Endothelin-1-induced NGF augmentation was mediated by the endothelin-A receptor, Gibetagamma, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein delta element. Either conditioned medium or coculture with endothelin-1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. NGF expression, cardiac sympathetic innervation, and norepinephrine concentration were specifically reduced in endothelin-1-deficient mouse hearts, but not in angiotensinogen-deficient mice. In endothelin-1-deficient mice the sympathetic stellate ganglia exhibited excess apoptosis and displayed loss of neurons at the late embryonic stage. Furthermore, cardiac-specific overexpression of NGF in endothelin-1-deficient mice overcame the reduced sympathetic innervation and loss of stellate ganglia neurons. These findings indicate that endothelin-1 regulates NGF expression in cardiomyocytes and plays a critical role in sympathetic innervation of the heart.

Prepubertal administration of estradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: role of sympathetic innervation.

Administration of estradiol valerate (EV) to adult rats leads to anovulation and cystic ovarian morphology. Sympathetic ovarian nerve denervation (SONX) overcomes this disruption. In this study, we determined whether EV administration to juvenile rats prevents achievement of reproductive competence, disrupts cyclicity, and whether this programming is facilitated via activation of the sympathetic nerve input to the ovary. Prepubertal rats were administered 2 mg EV in corn oil or corn oil alone. One half of the animals from each group underwent SONX on d 71 of life. Rats were euthanized on d 91 for determination of serum gonadotropins, progesterone, Delta4 androstenedione, and estradiol concentrations, ovarian norepinephrine (NE), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activities and ovarian dynamics. Results revealed that EV administration during juvenile period advanced pubertal onset, suppressed circulating LH, FSH, and Delta4 androstenedione, increased ovarian NE, estradiol, and 3beta-HSD activities, disrupted ovarian dynamics evidenced as absent corpus luteum and presence of ovarian cysts and culminated in anovulation. SONX restored cyclicity in these animals, normalized LH, estradiol, ovarian 3beta-HSD activities, and ovarian dynamics as evidenced by the disappearance of ovarian cysts and appearance of corpus luteum and restored corpus luteum function. These findings provide evidence that EV exposure during juvenile life leads to long-lasting deleterious reproductive consequences via activation of the sympathetic ovarian nerve.