Direct evidence of VEGF-mediated neuroregulation and afferent explanation of blood pressure dysregulation during angiogenic therapy

Objective Oncocardiology is increasingly hot research field/topic in the clinical management of cancer with anti-angiogenic therapy of vascular endothelial growth factor (VEGF) that may cause cardiovascular toxicity, such as hypertension via vascular dysfunction and attenuation of eNOS/NO signaling in the baroreflex afferent pathway. The aim of the current study was to evaluate the potential roles of VEGF/VEGF receptors (VEGFRs) expressed in the baroreflex afferent pathway in autonomic control of blood pressure (BP) regulation. Methods The distribution and expression of VEGF/VEGFRs were detected in the nodose ganglia (NG) and nucleus of tractus solitary (NTS) using immunostaining and molecular approaches. The direct role of VEGF was tested by NG microinjection under physiological and hypertensive conditions. Results Immunostaining data showed that either VEGF or VEGFR2/VEGFR3 was clearly detected in the NG and NTS of adult male rats. Microinjection of VEGF directly into the NG reduced the mean blood pressure (MBP) dose-dependently, which was less dramatic in renovascular hypertension (RVH) rats, suggesting the VEGF-mediated depressor response by direct activation of the 1st-order baroreceptor neurons in the NG under both normal and disease conditions. Notably, this reduced depressor response in RVH rats was directly caused by the downregulation of VEGFR2, which compensated the up regulation of VEGF/VEGFR3 in the NG during the development of hypertension. Conclusion It demonstrated for the first time that the BP-lowering property of VEGF/VEGFRs signaling via the activation of baroreflex afferent function may be a common target/pathway leading to BP dysregulation in anti-angiogenic therapy.

Vagus nerve stimulation increases stomach-brain coupling via a vagal afferent pathway

Maintaining energy homeostasis is vital and supported by vagal signaling between digestive organs and the brain. Previous research has established a gastric network in the brain that is phase synchronized with the rhythm of the stomach, but tools to perturb its function were lacking. Here, we investigated the effect of acute right-sided transcutaneous auricular vagus nerve stimulation (taVNS) versus sham stimulation (randomized crossover-design) on stomach-brain coupling. In line with preclinical research, taVNS increased stomach-brain coupling in the nucleus of the solitary tract (NTS) and the midbrain while boosting coupling across the brain. Crucially, in the cortex, taVNS-induced changes in coupling occurred primarily in transmodal regions and were associated with changes in hunger ratings as indicators of the subjective metabolic state. Hence, taVNS alters stomach-brain coupling via an NTS-midbrain pathway that signals gut-induced reward, potentially paving the way for novel treatments in disorders such as Parkinson's disease or depression.

Human milk oligosaccharide 2′-fucosyllactose supplementation improves gut barrier function and signaling in the vagal afferent pathway in mice

2’-Fucosyllactose (2’-FL), a predominant human milk oligosaccharide, attenuates HF diet-induced metabolic and intestinal barrier impairment, improves gut hormone resistance, and alters the intestinal microbiota and microbiota-derived metabolites.

Contribution of afferent pathway to vagal nerve stimulation-induced myocardial interstitial acetylcholine release in rats

Vagal nerve stimulation (VNS) has been explored as a potential therapy for chronic heart failure. The contribution of the afferent pathway to myocardial interstitial acetylcholine (ACh) release during VNS has yet to be clarified. In seven anesthetized Wistar-Kyoto rats, we implanted microdialysis probes in the left ventricular free wall and measured the myocardial interstitial ACh release during right VNS with the following combinations of stimulation frequency (F in Hz) and voltage readout (V in volts): F0V0 (no stimulation), F5V3, F20V3, F5V10, and F20V10. F5V3 did not affect the ACh level. F20V3, F5V10, and F20V10 increased the ACh level to 2.83 ± 0.47 ( P < 0.01), 4.31 ± 1.09 ( P < 0.001), and 4.33 ± 0.82 ( P < 0.001) nM, respectively, compared with F0V0 (1.76 ± 0.22 nM). After right vagal afferent transection (rVAX), F20V3 and F20V10 increased the ACh level to 2.90 ± 0.53 ( P < 0.001) and 3.48 ± 0.63 ( P < 0.001) nM, respectively, compared with F0V0 (1.61 ± 0.19 nM), but F5V10 did not (2.11 ± 0.24 nM). The ratio of the ACh levels after rVAX relative to before was significantly <100% in F5V10 (59.4 ± 8.7%) but not in F20V3 (102.0 ± 8.7%). These results suggest that high-frequency and low-voltage stimulation (F20V3) evoked the ACh release mainly via direct activation of the vagal efferent pathway. By contrast, low-frequency and high-voltage stimulation (F5V10) evoked the ACh release in a manner dependent on the vagal afferent pathway.

Management of Cough

Cough is the most frequent symptom for which patients consult with their health care provider throughout the world. This symptom could be happened not only in sick individuals but also healthy individuals. At some stage, it is distressing, inhibits normal social activities, and reduces quality of life. Besides these detrimental effects, cough is the most effective defense mechanism to eliminate foreign materials, including various pathogens, from the respiratory tract. It begins with a series of breathing maneuvers which triggers sudden expulsion of air which is divided into three phases, i.e. inspiration, compression, and expiration phase. Cough occurs due to activation of mechanical or chemical sensory receptors in the larynx and lower respiratory tract which stimulates reflex arc complex. This stimulus is then transmitted to the afferent pathway to the cough center in the medulla through the vagus nerve to trigger expiration muscles to produce cough. It is important to know the cause of cough because cough is an indicator for patients and doctors for early diagnosis and therapy of disease. Therefore, cough is classified into acute, subacute, and chronic according to its duration. Available medications for symptomatic management of cough are inadequate due to lack of proven efficacy and/or their undesirable or intolerable side effects. This article aims to provide information on cough management to improve therapeutic effectiveness and patient quality of life.