Celiac Ganglionectomy Research Articles

Abstract 16602: The PlGF-Nrp1 Interaction Promotes the Splenic Immune Response in Hypertension After Neuroimmune Activation

Introduction: We previously discovered that Placental Growth Factor (PlGF) is released in the spleen by a sympathetic discharge to elicit hypertension. Neuropilin1 (Nrp1) is one of PlGF receptors and, interestingly, is a transmembrane protein expressed on precursors of Dendritic cells (DCs). Hypothesis: Here we investigated the involvement of Nrp1 as the PlGF receptor mediating the neuroimmune activation of immune response during hypertension. Methods: We used flow cytometry and tail cuff to evaluate the involvement of PlGF-Nrp1 pathway in neuroimmune activation of splenic immune response in hypertension. Results: To define Nrp1 role in transducing PlGF effect during hypertension, we evaluate its expression by flow cytometry finding that monocyte-derived DCs (MoDCs) increased Nrp1 expression in response to AngII (12.7±1.3 vs 28.8±3 % Nrp1 Veh vs AngII; p<0.01). This effect was blocked by splenic sympathetic denervation obtained by celiac ganglionectomy (CGX) (28.8±3 vs 14±1.5 % Nrp1 Sham AngII vs CGX AngII; p<0.01). To test the relevance of PlGF-Nrp1 pathway in hypertension, we generated a transgenic mouse model with a selective deletion of Nrp1 in myeloid lineage utilizing the LysMcre (Nrp1 myeKO mice). By using an in vitro standard differentiation protocol of maturation of monocytes in DCs, we observed that CD86 and MHCII expression was up-regulated in MoDCs from the spleen of WT mice cultured in the standard medium plus rmPlGF (0.014±0.001 vs 0.035±0.005 CD86+ DCs/total cells count respectively, p<0.05; 0.010±0.003 vs 0.030±0.003 MHCII+ DCs/total cells count respectively, p<0.01). On the contrary, CD86 and MHCII were similarly expressed on MoDCs from Nrp1 myeKO mice cultured with and without rmPlGF indicating that PlGF is involved in the maturation of MoDCs through its interaction with Nrp1. To confirm the involvement of Nrp1 in blood pressure (BP) increase, we infused AngII to Nrp1 myeKO mice, finding that they were protected from hypertension as compared to WT control mice (Systolic BP 106±1 vs 126±2 mmHg respectively, p<0.001). Conclusions: These data demonstrate that PlGF-Nrp1 pathway is a key mechanism that promote the immune response involved in hypertension and blocking the splenic innervation, hampered this response and BP increase.

First description of a histopathologic grading system and relationship to outcomes after robotic median arcuate ligament release with celiac ganglionectomy and lymphadenectomy

BackgroundTwo dominating theories regarding median arcuate ligament syndrome include vascular and neurogenic etiologies from celiac artery and ganglion compression, respectively. Celiac ganglionectomy is not routine during surgery, and specimens are rarely excised; therefore, the extent of nerve involvement and histopathology are unknown. Our study aims to characterize histopathologic findings in median arcuate ligament syndrome, establish a histopathologic grading system, and correlate with clinical outcomes. MethodsRobotic median arcuate ligament release, celiac ganglionectomy, and lymphadenectomy were performed with specimens excised and stained using hematoxylin & eosin, trichrome, and S100. Neurofibrosis, adiposity, and reactive changes were described, a grading scale was developed, and results were analyzed with clinical outcomes. ResultsFifty-four patients were evaluated, of whom 36 met inclusion criteria (81% female, 34.9 [25.9–47.5] years, body mass index 23.5 [19.6–28.1] kg/m2). Histopathologic evaluation revealed fibrosis (hematoxylin & eosin and trichrome median score 1.5 [0–2.5]), reactive lymphadenopathy (89%), intraparenchymal nerves (31%), and lipogranulomas (31%). Greater fibrosis was associated with a lack of preoperative celiac plexus block relief (100% vs. 30%, P = .044) and lower postoperative celiac artery velocities (198 vs 323 cm/s, P = .02). Intraparenchymal nerves were associated with greater decreases in pre to postoperative velocities (161 vs 84 cm/s, P = .037). Symptoms improved in 28 patients (78%). ConclusionWe developed the first histopathologic grading system and identified unique findings of intraparenchymal nerves and lipogranulomas. Histopathologic abnormalities were associated with objective improvement and symptomatic relief postoperatively. These findings support nerve compression and inflammation as predominant contributors to median arcuate ligament syndrome pain, celiac ganglia resection to treat symptoms, and continued histopathologic analysis to better elucidate median arcuate ligament syndrome etiology.

Median Arcuate Ligament Syndrome: A 10-year Review of Management at a Tertiary Medical Center

Median arcuate ligament syndrome (MALS) was described decades ago; however, its diagnostic criteria and treatment paradigms remain unclear. Ligament release and celiac ganglionectomy can relieve symptoms, however only certain patients benefit. We sought to characterize the factors leading to operative management and its influence on outcomes at our institution.

Median Arcuate Ligament Release with Celiac Ganglionectomy for Management of Chronic Disabling Abdominal Pain in Patients With and Without Celiac Artery Compression - A Case Series

The current accepted surgical treatment for median arcuate ligament syndrome (MALS) is by division or release of the MAL (MALR), but current treatment strategies are known to remain inconsistently effective with variable recurrence rates. Treatment algorithms typically rely on the demonstration of celiac artery compression before offering patients surgical intervention. We sought to decrease reliance on abnormal arterial imaging as inclusion criteria and to see whether ganglionectomy in patients without celiac compression would provide symptom relief.

Hypothalamic Corticotrophin Releasing Hormone Signal Contributes to Elevated Sympathetic Outflow in primary hypertension

Corticotropin‐releasing hormone (CRH) is a neuropeptide involved in regulating neuroendocrine and autonomic function. CHR mRNA and protein expression in the hypothalamic paraventricular nucleus (PVN) are significantly increased in patients with primary hypertension. However, the role of CRH signals in elevated sympathetic outflow in primary remains unclear. Here, we showed that CRH receptor 1 (CRHR1) protein level rats was significantly increased in the PVN tissue in spontaneously hypertensive (SHR) compared with Wistar‐Kyoto (WKY). Upregulated CRHR1 level in the PVN was not significantly affected by lowing arterial blood pressure (ABP) by celiac ganglionectomy in SHRs. Immunocytochemistry staining revealed that CRHR1 immunoreactivities were in PVN neurons projecting to the rostral ventrolateral medulla (RVLM). Bath application of CRH induced a significantly greater increase in the firing rate of PVN‐RVLM projection neurons in SHRs than in WKY rats. Blocking CRHRs with astressin or CRHR1 with antalarmin significantly decreased firing rate of PVN‐RVLM projection neurons in SHR but not in WKY, while blocking CRHR2 with antisauvagine‐30 did not alter the firing rate of these neurons in SHR. Both antalarmin and antisauvagine‐30 did not change the frequency and amplitude of miniature inhibitory post‐synaptic currents or miniature excitatory post‐synaptic currents recorded in brain slice preparation of SHR and WKY rats. In addition, bilateral microinjection of CRH into the PVN produced a greater dose‐dependent increases in arterial blood pressure (ABP), renal sympathetic activity (RSNA), and heart rate (HR) in anesthetized SHRs than in WKY rats. Microinjection of CRHR1 antagonist NBI35965 into the PVN significantly reduced basal ABP, RSNA, and HR in SHRs but did not change ABP, RSNA, and HR in WKY rats. These data suggested that the upregulation of CRHR1 in the PVN is critically involved in elevated sympathetic outflow and hyperactivity of sympathetic‐related neurons in hypothalamus in primary hypertension.

Neuroimmune cardiovascular interfaces control atherosclerosis.

Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries(the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmunecardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased inparallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.

Median arcuate ligament syndrome (Dunbar syndrome).

Median arcuate ligament syndrome (MALS) is a rare condition which is due to the compression of celiac trunk by low riding of fibrous attachments of median arcuate ligament and diaphragmatic crura. Technically, MALS is a diagnosis of exclusion, consisting of vague symptoms comprising of postprandial epigastric pain, nausea, vomiting and unexplained weight loss. Different imaging modalities like Doppler ultrasound, computed tomography, magnetic resonance imaging and mesenteric angiogram are helpful to demonstrate celiac axis compression. The goal of treatment is decompression of celiac trunk either by open, laparoscopic or robotic method along with adjuvant interventional procedures like percutaneous transluminal angioplasty (PTA) and stenting. Surgical is the mainstay of treatment. This approach is based on open, laparoscopic or robotic release of compressed ligament along with celiac ganglionectomy and celiac artery revascularization. The role of interventional radiology is limited to angioplasty and stenting to open the stenosis rather than addressing the underlying compression of celiac trunk which has resulted in the symptoms. However, both the diagnosis and therapeutic intervention remains challenging. Extensive evaluation of etiology and pathophysiology of MALS and addressing the same through minimally invasive techniques may yield best prognosis in future. In this review article, we discuss briefly about the MALS in terms of etiology, diagnosis and its management including the role of interventional radiology.

Abstract No. 219 Rethinking median arcuate ligament syndrome: the role of celiac plexus block for diagnosis

To evaluate celiac plexus block (CPB) as a preoperative diagnostic tool for median arcuate ligament syndrome (MALS) A retrospective cohort study of 96 clinically diagnosed MALS patients that underwent 103 CT-guided percutaneous CPB at a single hospital between January 1, 2017, and April 3, 2020. Clinical, imaging, and procedural reports were reviewed. A CPB database was established. Numeric rating scale-11 was used to self-report pain scores. Primary outcomes were technical success, pain score, nausea, and vomiting. A total of 96 patients (75 female) with a mean age of 26.7 years. Computed tomography (CT) imaging was available for review in 81 of 96 patients. CT findings of MALS including low-lying median arcuate ligament, celiac artery stenosis, inferiorly displaced celiac trunk, or celiac trunk hook-shaped configuration was present in 22/81 patients. There were no differences in post-CPB pain relief between patients with normal anatomy findings versus MALS anatomy (P = .7447).Technical success was achieved in 102 of 103 cases. Postprandial pain score decreased from 6.3 to 0.9 points (P< .0001). Postprandial nausea decreased from 37.9% to 11.6% (P< .0001). Postprandial vomiting decreased from 15.5% to 4.9% (P = .0194). No major adverse events and one moderate adverse event were reported. Subsequently, 45.8% of patients elected to undergo MALS surgery: exploratory laparotomy with median arcuate ligament resection and celiac ganglionectomy. Patients electing for MALS surgery had significantly higher pre-CPB pain scores (7.0 versus 5.6 points, P = .023) and lower post-CPB pain scores (0.4 versus 1.3 points, P = .043) when compared to patients that did not pursue surgery. MALS is not an arteriopathy, but rather an autonomic neuropathy responsive to local anesthetic block. In our series of 103 CPB, we reported pain relief in 83.5%, regardless of CT findings of arterial involvement. The degree of response to CPB correlates with the decision to undergo MALS surgery. CPB is safe and central to the preoperative diagnosis of MALS.

Impaired Kv7 channel activity in the central amygdala contributes to elevated sympathetic outflow in hypertension.

Elevated sympathetic outflow is associated with primary hypertension. However, the mechanisms involved in heightened sympathetic outflow in hypertension are unclear. The central amygdala (CeA) regulates autonomic components of emotions through projections to the brainstem. The neuronal Kv7 channel is a non-inactivating voltage-dependent K+ channel encoded by KCNQ2/3 genes involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we investigated if altered Kv7 channel activity in the CeA contributes to heightened sympathetic outflow in hypertension. The mRNA and protein expression levels of Kv7.2/Kv7.3 in the CeA were significantly reduced in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto (WKY) rats. Lowering blood pressure with coeliac ganglionectomy in SHRs did not alter Kv7.2 and Kv7.3 channel expression levels in the CeA. Fluospheres were injected into the rostral ventrolateral medulla (RVLM) to retrogradely label CeA neurons projecting to the RVLM (CeA-RVLM neurons). Kv7 channel currents recorded from CeA-RVLM neurons in brain slices were much smaller in SHRs than in WKY rats. Furthermore, the basal firing activity of CeA-RVLM neurons was significantly greater in SHRs than in WKY rats. Bath application of specific Kv7 channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) increased the excitability of CeA-RVLM neurons in WKY rats, but not in SHRs. Microinjection of XE-991 into the CeA increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), while microinjection of Kv7 channel opener QO-58 decreased ABP and RSNA, in anaesthetized WKY rats but not SHRs. Our findings suggest that diminished Kv7 channel activity in the CeA contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new mechanistic insight into the pathogenesis of neurogenic hypertension.

Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice.

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (-11±2 mm Hg) and CGX (-11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (-5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (-10±5 mm Hg) compared with baseline control (-25±10 mm Hg). This was not the case in mice in the SHAM (day 10; -28±5 mm Hg) or CGX (day 10; -34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Ghrelin inhibits autonomic response to gastric distension in rats by acting on vagal pathway

Ghrelin is the only orexigenic peptide currently known and a potent prokinetic by promoting gastric motility but novel insights suggest that its role extends beyond satiety regulation. Whereas ghrelin was shown to provide somatic and colonic antinociception, its impact on gastric sensitivity is unknown even though stomach is a major ghrelin secreting tissue. Autonomic response to gastric mechanosensitivity was estimated by measuring blood pressure variation as a surrogate marker in response to gastric distension (GD) before and after ghrelin (or vehicle) administration. Involvement of spinal and vagal pathways in the ghrelin effect was studied by performing celiac ganglionectomy and subdiaphragmatic vagotomy respectively and by evaluating the expression of phosphorylated extracellular-regulated kinase 1/2 (p-ERK1/2) in dorsal root and nodose ganglia. Finally the phenotype of Ghrelin receptor expressing neurons within the nodose ganglia was determined by in situ hybridization and immunofluorescence. Ghrelin reduced blood pressure variation in response to GD except in vagotomized rats. Phosphorylated-ERK1/2 levels indicated that ghrelin reduced neuronal activation induced by GD in nodose ganglion. The effect of ghrelin on gastric mechanosensitivity was abolished by pre-treatment with antagonist [D-Lys3]-GHRP-6 (0.3 mg/kg i.v.). Immunofluorescence staining highlights the colocalization of Ghrelin receptor with ASIC3 and TRPV1 within gastric neurons of nodose ganglion. Ghrelin administration reduced autonomic response to gastric distension. This effect likely involved the Ghrelin receptor and vagal pathways.

Robotic-Assisted Median Arcuate Ligament Release

This video presents the case of a patient with median arcuate ligament syndrome, treated by robotic-assisted release and celiac ganglionectomy. Patient presentation, imaging, operative video, and postoperative course are discussed.

Downregulation of KCNQ channels in the CeA contributes to elevated sympathetic outflow in hypertension

Elevation of sympathetic outflow is associated with many hypertensive conditions. The central nucleus of amygdala (CeA) is crucial in the regulation of emotion, pain, and cardiovascular functions. The M‐channel is a non‐inactivating voltage‐dependent K+ channel stabilizing the membrane potential and mainly consists of heterotetrameric Kv7.2 and Kv7.3 subunits. However, the role of M channels in the CeA in heightened sympathetic vasomotor tone in hypertension remain unknown. Microinjecting of the specific M‐channel blocker XE‐991 into the CeA significantly increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) but did not alter heart rate (HR) in anesthetized Wistar Kyoto rats (WKY) rats. In spontaneously hypertensive rats (SHRs), microinjection of the same dose of XE‐991 into the CeA had no effect on ABP, RSNA, or HR in SHRs. On the other hand, microinjection of the M‐channel opener QO‐58 into the CeA decreased ABP and RSNA in WKY rats but failed to alter these cardiovascular variables in SHRs. The protein and mRNA levels of Kv7.2 and Kv7.3 in the CeA were significantly lower in SHRs than in WKY rats. Lowering ABP via celiac ganglionectomy in SHRs did not altered the expression levels of Kv7.2 and Kv7.3 in the CeA. In a brain slice preparation, the basal firing activity of labeled CeA‐RVLM projection neurons was significantly greater in SHRs than in WKY rats. Blocking M‐currents with XE‐991 increased both spontaneous and current injection‐evoked firing rate of CeA‐RVLM projection neurons in WKY rats but had no such effect in SHRs. Also, the M‐currents triggered by a membrane depolarization in CeA‐RVLM neurons were significantly smaller in SHRs than in WKY rats. These data suggest that M‐channel activity is impaired and leads to hyperactivity of CeA‐RVLM projection neurons, which contributes to elevated sympathetic vasomotor activity in hypertension.Support or Funding Information SupportThis study was supported by NIH grant HL139523 and HL142133.

Ileal cross transplantion between OVLT lesioned and sham rats alters OVLT‐sympathetic‐gut microbiome axis function in DOCA‐salt hypertension.

Recently, there has been growing interest in understanding the gut microbe‐host interaction in the maintenance of health or disease states, but relatively few studies have shown an association between the gut microbiome and specific types of hypertension. The deoxycorticosterone acetate (DOCA)‐salt hypertensive model in rats has a well described neurogenic component linked to increased sympathetic nervous system acitivity. As previously demonstrated by our laboratory, the hypertensive response in DOCA‐treated rats involves the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ that connects directly with the paraventricular nucleus (PVN) to increase sympathetic activity. In addition, it has been shown that celiac ganglionectomy supports a role of splanchnic innervation to the gut in the hypertensive response to DOCA. Indeed, we have previously shown that the OVLT plays a pivotal role in the development of DOCA‐salt hypertension. Moreover, we have also observed that this nucleus is able to mediate changes in the intestinal microbiome with the concomitant increase in blood pressure during DOCA salt hypertension. However, these changes were mitigated and offset by lesion of the OVLT and bacterial populations in OVLT lesioned rats with attenuated hypertension more closely resembled those in normal control rats. Therefore, we currently hypothesize that ileal transplantation from OVLT lesioned rats to SHAM operated rats will reverse or attenuate DOCA‐salt hypertension. Adult male Sprague‐Dawley rats were randomly selected for lesion of OVLT (OVLTx; n=3) or SHAM operation (OVLT SHAM; n=3), subsequently uninephrectomized and instrumented with telemetric blood pressure transducers as well as chronic indwelling ileal catheters. Rats were then subjected to DOCA‐salt for 16 days. 10 days after DOCA treatment, rats underwent daily ileal transplantation: approximately 2 ml of the ileal content was withdrawn from the ileal catheter in all rats and cross transplanted (between OVLTx and respective SHAM rats) on days 10–16 of DOCA treatment. Mean arterial pressure (MAP) was measured during 5 control days and 16 days of DOCA treatment. On days 3–6 and 9–10 of DOCA treatment, the chronic pressor response to DOCA was attenuated in OVLTx rats such that by Day 10 MAP increased to 125±1.8 mmhg in SHAM rats when compared to only 112±2.5 mmHg in OVLTx rats. After ileal cross transplantation, a progressive decrease in MAP in SHAM rats was observed. In fact, on the sixth day after transplantation, MAP was decreased to 114±1.2 mmHg in these animals, whereas in OVLTx rats MAP increased to 120±1.8 mmHg. Therefore, after ileal cross transplantation, a powerful reversal of the chronic hypertensive response was observed. Additionally, an opposite effect was observed in OVLTx rats in that blood pressure increased. These results support a prominent role of the OVLT‐sympathetic‐gut microbiome axis in the development of hypertension. As such, targeting these alterations in gut microbiota may have promising therapeutic potential to improve health and a role in the prevention and treatment of hypertension.Support or Funding InformationAmerican Heart Association Award: 19AIREA34380525

STRUCTURAL BASES OF GASTROINTESTINAL MOTILITY CHANGES IN PARKINSON’S DISEASE: STUDY IN RATS

ABSTRACT Background: Gastrointestinal disorders are frequently reported in patients with Parkinson’s disease whose disorders reduce the absorption of nutrients and drugs, worsening the clinical condition of patients. However, the mechanisms involved in modifying gastrointestinal pathophysiology have not yet been fully explained. Aim: To evaluate its effects on gastrointestinal motility and the involvement of the vagal and splanchnic pathways. Methods: Male Wistar rats (250-300 g, n = 84) were used and divided into two groups. Group I (6-OHDA) received an intrastriatal injection of 6-hydroxydopamine (21 µg/animal). Group II (control) received a saline solution (NaCl, 0.9%) under the same conditions. The study of gastric emptying, intestinal transit, gastric compliance and operations (vagotomy and splanchnotomy) were performed 14 days after inducing neurodegeneration. Test meal (phenol red 5% glucose) was used to assess the rate of gastric emptying and intestinal transit. Results: Parkinson’s disease delayed gastric emptying and intestinal transit at all time periods studied; however, changes in gastric compliance were not observed. The delay in gastric emptying was reversed by pretreatment with vagotomy and splanchnotomy+celiac gangliectomy, thus suggesting the involvement of such pathways in the observed motor disorders. Conclusion: Parkinson’s disease compromises gastric emptying, as well as intestinal transit, but does not alter gastric compliance. The delay in gastric emptying was reversed by truncal vagotomy, splanchnotomy and celiac ganglionectomy, suggesting the involvement of such pathways in delaying gastric emptying.

DOCA‐salt hypertension and the role of the OVLT‐sympathetic‐gut microbiome axis

Limited studies suggest an association of gut microbiome changes with certain forms of hypertension, but a cause/effect relationship has yet to be fully defined. The deoxycorticosterone acetate (DOCA)‐salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. Indeed, we have recently shown the hypertensive response in DOCA‐treated rats requires the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ that has direct connections to the PVN to increase sympathetic activity. Furthermore, celiac ganglionectomy also supports a role of splanchnic sympathetic innervation to the gut in the hypertensive response to DOCA. Taken together, we hypothesize an OVLT‐sympathetic‐gut (OSG) microbiome axis is involved in the development of hypertension. Having previously reported that the OVLT plays a significant role in the development of DOCA‐salt hypertension, the present study was designed to test the hypothesis that the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. In uninephrectomized OVLT lesioned (OVLTx; n = 5) and SHAM (n = 4) Sprague‐Dawley rats consuming a 2% NaCl diet and 0.9% NaCl drinking solution, 24‐hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). Microbiome analyses were performed on regional gut samples (jejunum, ileum, cecum, and colon) at the end of the study and compared to normal control rats (n=8). The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 157±7 mmHg in SHAM rats by Day 21 of DOCA compared to only 127±5 mmHg in OVLTx rats. Moreover, DOCA hypertension in SHAM rats was associated with decreased levels of Lactobacillus species in the ileum. However, these changes were mitigated and offset by lesion of the OVLT and these bacterial populations in OVLT lesioned rats with attenuated hypertension more closely resembled those in normal control rats. Using Spearman correlation, increasing blood pressure on day 21 correlated with increased Clostridia levels in all tissues, as well as increasing Prevotella and decreasing Bacteroides. We conclude that DOCA‐salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA‐salt in OVLT lesioned rats is mediated in part through counteracting changes in these bacterial populations.Support or Funding InformationSupported by Merial Veterinary Scholars Research Grant and University of Minnesota Grant In AidThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A case of negative computed tomography in liver transplant recipient with medium arcuate ligament syndrome (MALS). When to discard radiology in favor of surgical experience?

Introduction: MALS, also known as celiac axis compression syndrome or Dunbar syndrome, is a rare and nonspecific disorder, when the median arcuate ligament compresses the celiac trunk due to the abnormal position of either the celiac trunk or the median arcuate ligament. Diagnosis of MALS is confirmed with positive findings on computer tomography (CT) or magnetic resonance angiography combined with duplex ultrasonography (USG). MALS is treated with the surgical release of the median arcuate ligament and celiac ganglionectomy. Case: 41 year old female underwent a liver transplantation for unresectable epithelioid hemangioendothelioma. Following the transplantation, abdominal USG and CT showed no flow within the left and right hepatic arteries. No evident stricture in 3D CT reconstruction was found. Complete thrombosis of the common hepatic artery was assumed and the patient was retransplanted six days later. During retransplantation, blood flow through the initially thrombosed hepatic artery, was not achieved until the dissection of the median arcuate ligament. Conclusion: Duplex USG may be superior to CT for diagnosing MALS as it reveals real time images where functional compression may be the case. When patient performs full expiration, USG shows this compression, if present, on the celiac trunk. CT during full inspiration will commonly show undisturbed arterial alignment and blood flow. Early diagnosis and treatment of MALS is a graft saving procedure. The surgeon should bare in mind that it’s the patient we ought to treat and not the radiology.

Abstract 132: Obesity-Related Hypertension Develops Through Splenic Sympathetic Overactivity and is Mediated by Immune-Modulating Functions of Placental Growth Factor

Obesity-related hypertension (HTN) is an epidemic health problem and a major risk factor for the development of cardiovascular disease. A consistent amount of research on the pathophysiological basis of obesity has implicated a crucial role of sympathetic overdrive. Interestingly, an overactivation of the sympathetic nervous system (SNS) accompanies HTN as well. Recent data highlighted that increased SNS activation in HTN is important in modulating immune responses, besides controlling typical cardiovascular functions. Whether neuroimmune mechanisms are relevant in obesity-induced HTN is still unknown. To test this hypothesis we subjected 6 week-old C57Bl/6J mice to high fat diet (HFD), as compared to low fat diet (LFD) and monitored blood pressure (BP), which started to rise after 2 months and steadily increased up to 4 months. We measured circulating noradrenalin, finding it significantly elevated 2 months after HFD. To gain insights in the potential SNS modulation of immunity, we measured by microneurography SNS activation on the splenic nerve. Firing frequency (FF, spikes in 10') of splenic nerve was increased in C57Bl/6J mice on HFD (FF:432±81) as compared to LFD (FF:86±10, p&lt;0.01). Then, we surgically removed splenic innervation by left celiac ganglionectomy (CGX) and fed mice with HFD for 4 months. Despite CGX-mice become obese similarly to sham, as shown by body weight and microCT-measured fat pad, they were protected from HTN (SBP mmHg =CGX:105±4; sham:125±5, p&lt;0.001), suggesting that the splenic sympathetic overdrive influences BP responses but not metabolic alterations. To look for molecular determinants, we analyzed the expression of Placental Growth Factor (PlGF), previously identified as a neuroimmune mediator, and found it significantly increased in the spleen upon HFD, but only with intact SNS innervation, since CGX-mice did not increase it. In the end, PlGF KO mice subjected to HFD, although becoming obese as much as WT, were protected from HTN (SBP mmHg =PlGF KO:103±4; WT:123±6, p&lt;0.001). Interestingly, both CGX and PlGF KO mice displayed a reduced egression of activated T cells from the spleen upon HFD feeding, suggesting that the protection observed could be related to reduced infiltration of activated lymphocytes in target organs.

Role of the OVLT‐gut microbiome axis on the development of DOCA‐salt hypertension

Limited studies suggest an association of gut microbiome changes with certain forms of hypertension, but a cause/effect relationship has yet to be fully defined. The deoxycorticosterone acetate (DOCA)‐salt model of hypertension in rats is known to have a neurogenic component linked to increased sympathetic nervous system activity. Indeed, we have recently shown the hypertensive response in DOCA‐treated rats requires the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ that has direct connections to the paraventricular nucleus (PVN) to increase sympathetic activity. Furthermore, celiac ganglionectomy also supports a role of splanchnic sympathetic innervation to the gut in the hypertensive response to DOCA. Taken together, we hypothesize an OVLT‐sympathetic‐gut (OSG) microbiome axis is involved in the development of hypertension. Having previously reported that the OVLT plays a significant role in the development of DOCA‐salt hypertension, the present study was designed to test the hypothesis that the OVLT mediates changes in the gut microbiome associated with concomitant hypertension. In uninephrectomized OVLT lesioned (OVLTx; n = 5) and SHAM (n = 2) Sprague‐Dawley rats consuming a 2% NaCl diet and 0.9% NaCl drinking solution, 24‐hour mean arterial pressure (MAP) was recorded telemetrically 5 days before and 21 days after DOCA implantation (100 mg/rat; SQ). Microbiome analyses were performed on regional gut samples at the end of the study and compared to normal rats (n=2). The chronic pressor response to DOCA was attenuated in OVLTx rats such that MAP increased to 153±4 mmHg in SHAM rats by Day 21 of DOCA compared to 127±5 mmHg in OVLTx rats. Moreover, DOCA hypertension in SHAM rats was associated with decreased levels of Lactobacillus species in the jejunum and ileum, and increased Escherichia levels in the cecum compared with normal rats. However, these changes in bacterial genera were mitigated and offset by lesion of the OVLT and these bacterial populations in OVLT lesioned rats with attenuated hypertension more closely resembled those in normal control rats. We conclude that DOCA‐salt hypertension is associated with specific microbiome changes in the gut, and the attenuated hypertensive effects of DOCA‐salt in OVLT lesioned rats is mediated in part through counteracting changes in these bacterial populations.Support or Funding InformationUniversity of Minnesota Grant‐In‐Aid # 107426This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Dual autonomic inhibitory action of central Apelin on gastric motor functions in rats.

Centrally administered apelin has been shown to inhibit gastric emptying (GE) in rodents, however, the relevant mechanism has been investigated incompletely. Using male Wistar rats, we investigated the efferent pathways involved in gastroinhibitory action of central apelin. Stereotaxic intracerebroventricular (icv) cannulation, subdiaphragmatic vagotomy (VGX) and/or celiac ganglionectomy (CGX) were performed 7 days prior to the experiments. Apelin-13 was administered (30 nmol, icv) 90 min prior to GE measurement. Nitric oxide synthase inhibitor L-NAME (100 mg/kg), sympatholytic agent guanethidine (5 mg/kg) and/or muscarinic receptor agonist bethanechol (1 mg/kg) were administered intraperitoneally 30 min prior to the central apelin-13 injection. Two strain gages were implanted serosally onto antrum and pylorus to monitor gastric postprandial motility. Heart rate variability (HRV) analysis was performed before and after central vehicle or apelin-13 administration. Apelin-13 delayed solid GE significantly by disturbing coordinated antral and pyloric postprandial contractions. The apelin-induced delayed GE was attenuated partially by CGX or VGX, whereas it was restored completely in rats underwent both CGX and VGX. L-NAME did not change the apelin-induced alterations. Guanethidine or bethanechol restored the apelin-induced gastroinhibition partially, while it was abolished completely in rats received both agents. Apelin-13 decreased the HRV spectral activity in high-frequency range by increasing low-frequency component and the ratio of LF:HF. The present data suggest that (1) both vagal parasympathetic and sympathetic pathways play a role in apelin-induced gastroinhibition, (2) central apelin attenuates vagal cholinergic pathway rather than activating nonadrenergic-noncholinergic pathway. Apelin/APJ receptor system might be candidate for the treatment of autonomic dysfunction and gastrointestinal motor disorders.