Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons

During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the endothelin family member Edn3 (ref. 1), acting through the endothelin receptor EdnrA (refs 2, 3), directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and have broad implications for endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62906/1/nature06859.pd

Pathophysiology of the endothelin system - lessons from genetically manipulated animal models

Shortly after discovery of ET-1 in 1988, the entire endothelin system was characterized. The endothelin system consists of the three peptides ET-1, ET-2 and ET-3, their G-protein-coupled receptors endothelin receptor A and B (ETRA and ETRB) and the two endothelin-converting enzymes (ECE-1 and ECE-2). Genetically modified animal models are an important tool in biomedical research. Here we describe the key findings obtained from genetically modified animal models either over-expressing compounds of the ET system or lacking these compounds (knockout mice). Results from the different transgenic and knockout models disclose that the ET system plays a major role in embryonic development. Two ET system-dependent neural crest-driven developmental pathways become obvious: one of them being an ET-1/ETAR axis, responsible for cardio-renal function and development as well as cranial development; the other seems to be an ET-3/ETBR mediated signalling pathway. Mutations within this axis are associated with disruptions in epidermal melanocytes and enteric neurons. These findings led to the discovery of similar findings in humans with Hirschsprung disease. In adult life the ET system is most important in the cardiovascular system and plays a role in fibrotic remodelling of the heart, lung and kidney as well as in the regulation of water and salt excretion

Role of 20-Hydroxyeicosatetraenoic Acid in Mediating Hypertension in Response to Chronic Renal Medullary Endothelin Type B Receptor Blockade

BACKGROUND: The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production. METHODOLOGY/PRINCIPAL FINDINGS: The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor. CONCLUSION: These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla

Genetic Background Strongly Modifies the Severity of Symptoms of Hirschsprung Disease, but Not Hearing Loss in Rats Carrying Ednrbsl Mutations

Hirschsprung disease (HSCR) is thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. However, it remains unknown whether the single complete deletion of important HSCR-associated genes is sufficient to result in HSCR disease. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrbsl mutations. Moreover, we found that this mutation results in serious congenital sensorineural deafness, and these strains may be used as ideal models of Waardenburg Syndrome Type 4 (WS4). Furthermore, we evaluated how the same changed genetic background modifies three features of WS4 syndrome, aganglionosis, hearing loss, and pigment disorder in these congenic strains. We found that the same genetic background markedly changed the aganglionosis, but resulted in only slight changes to hearing loss and pigment disorder. This provided the important evidence, in support of previous studies, that different lineages of neural crest-derived cells migrating along with various pathways are regulated by different signal molecules. This study will help us to better understand complicated diseases such as HSCR and WS4 syndrome

Direct costs of acute recurrent and chronic pancreatitis in children in the INSPPIRE registry

Objective: To estimate selected direct medical care costs of children with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). Methods: We performed a cross-sectional study of data from International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE), a multinational registry of children with ARP or CP. We determined health care utilization and estimated costs of hospitalizations, surgical and endoscopic procedures, and medications in our study population. Health care utilization data were obtained from all subjects enrolled in the study, and costs were calculated using national United States costs. Results: We included 224 subjects (median age 12.7 years), 42% of whomhad CP. Mean number of hospitalizations, including for surgery and endoscopic retrograde cholangiopancreatography, was 2.3 per person per year, costing an estimated average $38,755 per person per year. Including outpatient medications, estimated total mean cost was$40,589 per person per year. Subjects using surgical procedures or endoscopic retrograde cholangiopancreatography incurred mean annual costs of $42,951 per person and$12,035 per person, respectively. Estimated annual costs of pancreatic enzyme replacement therapy, diabetic medications, and painmedicationswere $4114,$1761, and $614 per person, respectively. In an exploratory analysis, patients with the following characteristics appear to accrue higher costs than those without them: more frequent ARP attacks per year, reported constant or episodic pain, family history of pancreatic cancer, and use of pain medication. Conclusions: ARP and CP are uncommon childhood conditions. The severe burden of disease associated with these conditions and their chronicity results in high health care utilization and costs. Interventions that reduce the need for hospitalization could lower costs for these children and their families