UNASSIGNED: Neurogenic hypertension (HTN) is a type of HTN characterized by increased activity of the sympathetic nervous system. Vascular compression is one of the pathogenic mechanisms of neurogenic HTN. Despite Jannetta\'s solid anatomical and physiological arguments in favor of neurogenic HTN in the 1970\'s, the treatment for essential HTN by microvascular decompression (MVD) still lacks established selection criteria. Therefore, the subjects selected for our center were limited to patients with primary trigeminal neuralgia (TN) and primary hemifacial spasm (HFS) of the vertebral/basilar artery (VA/BA) responsible vessel type coexisting with neurogenic HTN who underwent MVD of the brainstem to further explore possible indications for MVD in the treatment of neurogenic HTN.
UNASSIGNED: A retrospective analysis of 63 patients who were diagnosed with neurogenic HTN had symptoms of HFS and TN cranial nerve disease. Patients were treated at our neurosurgery department from January 2018 to January 2023. A preoperative magnetic resonance examination of the patients revealed the presence of abnormally located vascular compression in the rostral ventrolateral medulla (RVLM) and the root entry zone (REZ) of the IX and X cranial nerves (CN IX- X).
UNASSIGNED: There was no significant difference between the two groups in terms of gender, age, course of HFS, course of TN, course of HTN, degree of HTN, or preoperative blood pressure. Based on the postoperative blood pressure levels, nine out of 63 patients were cured (14.28%), eight cases (12.70%) showed a marked effect, 16 cases (25.40%) were effective, and 30 cases were invalid (47.62%). The overall efficacy was 52.38%. However, 39 cases of combined cranial nerve disease were on the left side of the efficacy rate (66.67%) and 24 cases of combined cranial nerve disease were on the right side of the efficacy rate (29.16%).
UNASSIGNED: Over the last few decades, many scholars have made pioneering progress in the clinical retrospective study of MVD for neurogenic hypertension, and our study confirms the efficacy of MVD in treating vertebral/basilar artery-type neurogenic hypertension by relieving the vascular pressure of RVLM. In the future, with the development and deepening of pathological mechanisms and clinical observational studies, MVD may become an important treatment for neurogenic hypertension by strictly grasping the surgical indications.
UNASSIGNED: MVD is an effective treatment for neurogenic HTN. Indications may include the following: left-sided TN or HFS combined with neurogenic HTN; VA/BA compression in the left RVLM and REZ areas on MRI; and blood pressure in these patients cannot be effectively controlled by drugs.

Elevated brain angiotensin II activity plays a key role in the development of neurogenic hypertension. While blood pressure (BP) control in neurogenic hypertension has been successfully demonstrated by regulating central angiotensin II activity, current techniques involving cerebrovascular injections of potential therapeutic agents are not suitable for clinical translation. To address this gap, we present the synthesis of dual-functionalized liposomes functionalized with targeting ligand and cell-penetrating peptide. Functionalized liposomes were synthesized using the thin film hydration technique and loaded with plasmid DNA encoding short hairpin RNA targeted toward angiotensin II receptors (PEAS), via the post-insertion method. The synthesized liposomes had a cationic surface charge, an average size of 150 nm, and effectively entrapped more than 89% of loaded PEAS. These liposomes loaded with PEAS demonstrated biocompatibility and efficient delivery to brain-derived cell lines, resulting in a remarkable reduction of more than 70% in receptor expression within 7 days. To assess the therapeutic potential, spontaneously hypertensive rats were administered intravenous injections of functionalized liposomes loaded with PEAS, and the changes in mean arterial pressure were monitored for 45 days. Remarkably, this treatment led to a significant (p < 0.001) decrease in BP of more than 30 mm Hg compared with saline-treated rats.

Hypertension is a major adverse effect of calcineurin inhibitors, such as tacrolimus (FK506) and cyclosporine, used clinically as immunosuppressants. Calcineurin inhibitor-induced hypertension (CIH) is linked to augmented sympathetic output from the hypothalamic paraventricular nucleus (PVN). GluA2-lacking, Ca2+-permeable AMPA receptors (CP-AMPARs) are a key feature of glutamatergic synaptic plasticity, yet their role in CIH remains elusive. Here, we found that systemic administration of FK506 in rats significantly increased serine phosphorylation of GluA1 and GluA2 in PVN synaptosomes. Strikingly, FK506 treatment reduced GluA1/GluA2 heteromers in both synaptosomes and endoplasmic reticulum-enriched fractions from the PVN. Blocking CP-AMPARs with IEM-1460 induced a larger reduction of AMPAR-mediated excitatory postsynaptic current (AMPAR-EPSC) amplitudes in retrogradely labelled, spinally projecting PVN neurons in FK506-treated rats than in vehicle-treated rats. Furthermore, FK506 treatment shifted the current-voltage relationship of AMPAR-EPSCs from linear to inward rectification in labelled PVN neurons. FK506 treatment profoundly enhanced physical interactions of α2δ-1 with GluA1 and GluA2 in the PVN. Inhibiting α2δ-1 with gabapentin, α2δ-1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C terminus peptide restored GluA1/GluA2 heteromers in the PVN and diminished inward rectification of AMPAR-EPSCs in labelled PVN neurons induced by FK506 treatment. Additionally, microinjection of IEM-1460 or α2δ-1 C terminus peptide into the PVN reduced renal sympathetic nerve discharges and arterial blood pressure elevated in FK506-treated rats but not in vehicle-treated rats. Thus, calcineurin in the hypothalamus constitutively regulates AMPAR subunit composition and phenotypes by controlling GluA1/GluA2 interactions with α2δ-1. Synaptic CP-AMPARs in PVN presympathetic neurons contribute to augmented sympathetic outflow in CIH. KEY POINTS: Systemic treatment with the calcineurin inhibitor increases serine phosphorylation of synaptic GluA1 and GluA2 in the PVN. Calcineurin inhibition enhances the prevalence of postsynaptic Ca2+-permeable AMPARs in PVN presympathetic neurons. Calcineurin inhibition potentiates α2δ-1 interactions with GluA1 and GluA2, disrupting intracellular assembly of GluA1/GluA2 heterotetramers in the PVN. Blocking Ca2+-permeable AMPARs or α2δ-1-AMPAR interactions in the PVN attenuates sympathetic outflow augmented by the calcineurin inhibitor.

Multiple sclerosis (MS) is an autoimmune demyelinating neurological disorder primarily manifesting with a range of neurological symptoms, with cardiovascular autonomic involvement being a rare occurrence. We report a case where a patient initially presented with Bell\'s palsy, without other notable symptoms or signs, and subsequently developed atrial fibrillation, hypertension, and hemiparesis. Magnetic resonance imaging (MRI) revealed extensive demyelination in the cerebral hemispheres, brainstem, and notably, the area postrema. The anatomy of the area postrema and its connections, in relation to neurogenic hypertension, are discussed. The demyelination in the area postrema was thought to be the cause of our patient\'s arrhythmias and acute hypertension. Furthermore, we discuss the cerebral origins of cardiac arrhythmias, with a focus on MS and other neurological conditions. This case underscores the rarity of isolated cranial neuropathies, such as Bell\'s palsy, as an initial sign of MS, marking the onset of a relapse.

Neurovascular compression of the rostral ventrolateral medulla (RVLM) has been described as a possible cause of refractory essential hypertension. We present the case of a patient affected by episodes of severe paroxysmal hypertension, some episodes associated with vago-glossopharyngeal neuralgia. Classical secondary forms of hypertension were excluded. Imaging revealed a neurovascular conflict between the posterior inferior cerebellar artery (PICA) and the ventrolateral medulla at the level of the root entry zone of the ninth and tenth cranial nerves (CN IX-X REZ). A MVD of a conflict between the PICA and the RVLM and adjacent CN IX-X REZ was performed, resulting in reduction of the frequency and severity of the episodes. Brain MRI should be performed in cases of paroxysmal hypertension. MVD can be considered in selected patients.

Increased expression of angiotensin II AT1A receptor (encoded by Agtr1a) and Na+-K+-Cl- cotransporter-1 (NKCC1, encoded by Slc12a2) in the hypothalamic paraventricular nucleus (PVN) contributes to hypertension development. However, little is known about their transcriptional control in the PVN in hypertension. DNA methylation is a critical epigenetic mechanism that regulates gene expression. Here, we determined whether transcriptional activation of Agtr1a and Slc12a2 results from altered DNA methylation in spontaneously hypertensive rats (SHR). Methylated DNA immunoprecipitation and bisulfite sequencing-PCR showed that CpG methylation at Agtr1a and Slc12a2 promoters in the PVN was progressively diminished in SHR compared with normotensive Wistar-Kyoto rats (WKY). Chromatin immunoprecipitation-quantitative PCR revealed that enrichment of DNA methyltransferases (DNMT1 and DNMT3A) and methyl-CpG binding protein 2, a DNA methylation reader protein, at Agtr1a and Slc12a2 promoters in the PVN was profoundly reduced in SHR compared with WKY. By contrast, the abundance of ten-eleven translocation enzymes (TET1-3) at Agtr1a and Slc12a2 promoters in the PVN was much greater in SHR than in WKY. Furthermore, microinjecting of RG108, a selective DNMT inhibitor, into the PVN of WKY increased arterial blood pressure and correspondingly potentiated Agtr1a and Slc12a2 mRNA levels in the PVN. Conversely, microinjection of C35, a specific TET inhibitor, into the PVN of SHR markedly reduced arterial blood pressure, accompanied by a decrease in Agtr1a and Slc12a2 mRNA levels in the PVN. Collectively, our findings suggest that DNA hypomethylation resulting from the DNMT/TET switch at gene promoters in the PVN promotes transcription of Agtr1a and Slc12a2 and hypertension development.

Neurogenic hypertension stems from an imbalance in autonomic function that shifts the central cardiovascular control circuits toward a state of dysfunction. Using the female spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat model, we compared the transcriptomic changes in three autonomic nuclei in the brainstem, nucleus of the solitary tract (NTS), caudal ventrolateral medulla, and rostral ventrolateral medulla (RVLM) in a time series at 8, 10, 12, 16, and 24 wk of age, spanning the prehypertensive stage through extended chronic hypertension. RNA-sequencing data were analyzed using an unbiased, dynamic pattern-based approach that uncovered dominant and several subtle differential gene regulatory signatures. Our results showed a persistent dysregulation across all three autonomic nuclei regardless of the stage of hypertension development as well as a cascade of transient dysregulation beginning in the RVLM at the prehypertensive stage that shifts toward the NTS at the hypertension onset. Genes that were persistently dysregulated were heavily enriched for immunological processes such as antigen processing and presentation, the adaptive immune response, and the complement system. Genes with transient dysregulation were also largely region-specific and were annotated for processes that influence neuronal excitability such as synaptic vesicle release, neurotransmitter transport, and an array of neuropeptides and ion channels. Our results demonstrate that neurogenic hypertension is characterized by brainstem region-specific transcriptomic changes that are highly dynamic with significant gene regulatory changes occurring at the hypertension onset as a key time window for dysregulation of homeostatic processes across the autonomic control circuits.NEW & NOTEWORTHY Hypertension is a major disease and is the primary risk factor for cardiovascular complications and stroke. The gene expression changes in the central nervous system circuits driving hypertension are understudied. Here, we show that coordinated and region-specific gene expression changes occur in the brainstem autonomic circuits over time during the development of a high blood pressure phenotype in a rat model of human essential hypertension.

Maternal protein malnutrition during developmental periods might impair the redox state and the brain\'s excitatory/inhibitory neural network, increasing central sympathetic tone. Conversely, moderate physical exercise at an early age reduces the risk of chronic diseases. Thus, we hypothesized that a moderate training protocol could reduce the harmful effects of a low-protein maternal diet on the brainstem of young male offspring. We used a rat model of maternal protein restriction during the gestational and lactation period followed by an offspring\'s continuous treadmill exercise. Pregnant rats were divided into two groups according to the protein content in the diet: normoprotein (NP), receiving 17% of casein, and low protein (LP), receiving 8% of casein until the end of lactation. At 30 days of age, the male offspring were further subdivided into sedentary (NP-Sed and LP-Sed) or exercised (NP-Ex and LP-Ex) groups. Treadmill exercise was performed as follows: 4 weeks, 5 days/week, 60 min/day at 50% of maximal running capacity. The trained animals performed a treadmill exercise at 50% of the maximal running capacity, 60 min/day, 5 days/week, for 4 weeks. Our results indicate that a low-protein diet promotes deficits in the antioxidant system and a likely mitochondrial uncoupling. On the other hand, physical exercise restores the redox balance, which leads to decreased oxidative stress caused by the diet. In addition, it also promotes benefits to GABAergic inhibitory signaling. We conclude that regular moderate physical exercise performed in youthhood protects the brainstem against changes induced by maternal protein restriction.

Neurogenic hypertension, a complex and multifactorial cardiovascular disorder, is known to be influenced by various genetic, environmental, and lifestyle factors. In recent years, there has been growing interest in the role of the gut microbiome in hypertension pathogenesis. The bidirectional communication between the gut microbiota and the central nervous system, known as the microbiota-gut-brain axis, has emerged as a crucial mechanism through which the gut microbiota exerts its influence on neuroinflammation, immune responses, and blood pressure regulation. Recent studies have shown how the microbiome has a substantial impact on a variety of physiological functions, such as cardiovascular health. The increased sympathetic activity to the gut may cause microbial dysbiosis, increased permeability of the gut, and increased inflammatory reactions by altering a number of intestinal bacteria producing short-chain fatty acids (SCFAs) and the concentrations of lipopolysaccharide (LPS) in the plasma. Collectively, these microbial metabolic and structural compounds stimulate sympathetic stimulation, which may be an important stage in the onset of hypertension. The result is an upsurge in peripheral and central inflammatory response. In addition, it has recently been shown that a link between the immune system and the gut microbiota might play a significant role in hypertension. The therapeutic implications of the gut microbiome including probiotic usage, prebiotics, dietary modifications, and fecal microbiota transplantation in neurogenic hypertension have also been found. A large body of research suggests that probiotic supplementation might help reduce chronic inflammation and hypertension that have an association with dysbiosis in the gut microbiota. Overall, this review sheds light on the intricate interplay between the gut microbiome and neurogenic hypertension, providing valuable insights for both researchers and clinicians. As our knowledge of the microbiome\'s role in hypertension expands, novel therapeutic strategies and diagnostic biomarkers may pave the way for more effective management and prevention of this prevalent cardiovascular disorder. Exploring the potential of the microbiome in hypertension offers an exciting avenue for future research and offers opportunities for precision medicine and improved patient care.

The main question of this chapter is as follows: What is the contribution of changes in the sympathetic-respiratory coupling to the hypertension observed in some experimental models of hypoxia? Although there is evidence supporting the concept that sympathetic-respiratory coupling is increased in different models of experimental hypoxia [chronic intermittent hypoxia (CIH) and sustained hypoxia (SH)], it was also observed that in some strains of rats and in mice, these experimental models of hypoxia do not affect the sympathetic-respiratory coupling and the baseline arterial pressure. The data from studies performed in rats (different strains, male and female, and in the natural sleep cycle) and mice submitted to chronic CIH or SH are critically discussed. The main message from these studies performed in freely moving rodents and in the in situ working heart-brainstem preparation is that experimental hypoxia changes the respiratory pattern, which correlates with increased sympathetic activity and may explain the hypertension observed in male and female rats previously submitted to CIH or SH.