Small vessel disease to subcortical dementia: a dynamic model, which interfaces aging, cholinergic dysregulation and the neurovascular unit.

BACKGROUND: Small vessels have the pivotal role for the brain's autoregulation. The arteriosclerosis-dependent alteration of the brain perfusion is one of the major determinants in small vessel disease. Endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia (sVAD). sVAD increases morbidity and disability. Epidemiological studies have shown that sVAD shares with cerebrovascular disease most of the common risk factors. The molecular basis of this pathology remains controversial. PURPOSE: To detect the possible mechanisms between small vessel disease and sVAD, giving a broad vision on the topic, including pathological aspects, clinical and laboratory findings, metabolic process and cholinergic dysfunction. METHODS: We searched MEDLINE using different search terms ("vascular dementia", "subcortical vascular dementia", "small vessel disease", "cholinergic afferents", etc). Publications were selected from the past 20 years. Searches were extended to Embase, Cochrane Library, and LILIACS databases. All searches were done from January 1, 1998 up to January 31, 2018. RESULTS: A total of 560 studies showed up, and appropriate studies were included. Associations between traditional vascular risk factors have been isolated. We remarked that SVD and white matter abnormalities are seen frequently with aging and also that vascular and endothelium changes are related with age; the changes can be accelerated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors. CONCLUSION: Small vessel disease and the related dementia are two pathologies that deserve attention for their relevance and impact in clinical practice. Hypertension might be a historical problem for SVD and SVAD, but low pressure might be even more dangerous; CBF regional selective decrease seems to be a critical factor for small vessel disease-related dementia. In those patients, endothelium damage is a super-imposed condition. Several issues are still debatable, and more research is needed.

Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia. NEW & NOTEWORTHY: Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory.

Depolarization of mitochondria in neurons promotes activation of nitric oxide synthase and generation of nitric oxide.

The diverse signaling events following mitochondrial depolarization in neurons are not clear. We examined for the first time the effects of mitochondrial depolarization on mitochondrial function, intracellular calcium, neuronal nitric oxide synthase (nNOS) activation, and nitric oxide (NO) production in cultured neurons and perivascular nerves. Cultured rat primary cortical neurons were studied on 7-10 days in vitro, and endothelium-denuded cerebral arteries of adult Sprague-Dawley rats were studied ex vivo. Diazoxide and BMS-191095 (BMS), activators of mitochondrial KATP channels, depolarized mitochondria in cultured neurons and increased cytosolic calcium levels. However, the mitochondrial oxygen consumption rate was unaffected by mitochondrial depolarization. In addition, diazoxide and BMS not only increased the nNOS phosphorylation at positive regulatory serine 1417 but also decreased nNOS phosphorylation at negative regulatory serine 847. Furthermore, diazoxide and BMS increased NO production in cultured neurons measured with both fluorescence microscopy and electron spin resonance spectroscopy, which was sensitive to inhibition by the selective nNOS inhibitor 7-nitroindazole (7-NI). Diazoxide also protected cultured neurons against oxygen-glucose deprivation, which was blocked by NOS inhibition and rescued by NO donors. Finally, BMS induced vasodilation of endothelium denuded, freshly isolated cerebral arteries that was diminished by 7-NI and tetrodotoxin. Thus pharmacological depolarization of mitochondria promotes activation of nNOS leading to generation of NO in cultured neurons and endothelium-denuded arteries. Mitochondrial-induced NO production leads to increased cellular resistance to lethal stress by cultured neurons and to vasodilation of denuded cerebral arteries.

[Pathophysiology of cluster headache]. / Physiopathologie de l'algie vasculaire de la face (AVF).

The aetiology of cluster headache is partially unknown. Three areas are involved in the pathogenesis of cluster headache: the trigeminal nociceptive pathways, the autonomic system and the hypothalamus. The cluster headache attack involves activation of the trigeminal autonomic reflex. A dysfunction located in posterior hypothalamic gray matter is probably pivotal in the process. There is a probable association between smoke exposure, a possible genetic predisposition and the development of cluster headache.

Effect of integrin combined laminin on peripheral blood vessel of cerebral infarction and endogenous nerve regeneration.

The third Chinese nationwide survey on causes of death states that cerebrovascular disease, accounting for 22.45% of total deaths, ranks as the first cause of death among rural and urban residents. It has become a serious public health problem since it has the highest disability and fatality rate among single diseases. Cerebral infarction is the most common cerebrovascular disease. In order to enhance the treatment response of cerebral infarction, this paper established male Sprague Dawley (SD) rat reperfusion model with 2 h of cerebral artery embolism by suture method. Neurological function deficit was scored according to rat improvement 24 h after model establishment, and 50 rats with scores between 10 and 13 were included in an ultimate experiment and were randomly divided into 5 groups: undisturbed control group, vascular endothelial growth factor (VEGF) up-regulated vessel group, endostatin down-regulated vessel group, ventricle injected Cxc Chemokin Receptor 4 (CXCR4) antibody group, ventricle injected α6ß1 antagonist (GoH3 antibody) group, respectively. The experiment was initiated after grouping and measurement of the relative data. The obtained results showed that the behavioral recovery of the VEGF group was more obvious compared with the control group, and the differences were statistically significant. The research was carried out using decreased modified neurological severity scores (mNSS), and the time a rat took to remove a pasted object. However, the behavioral recovery in the endostatin group, anti-CXCR4 group and GoH3 group was slow, and the difference was statistically significant, which showed as slowly decreased mNSS scoring and inconspicuous improved time of a rat removing a sticker. Compared with the control group, the number of peripheral BrdU+/ vWF+ cells of rat cerebral infarction in the VEGF group increased, and the peripheral VEGF expression quantity of cerebral infarction increased, thus the difference was statistically significant. However, cells in the endostatin group, anti-CXCR4 group, and GoH3 group were fewer and VEGF expression was reduced, and the difference was statistically significant. All these findings suggest that the promotion of angiogenesis after cerebral infarction can better provide the vascular niche for the proliferation, migration and differentiation of neural stem/progenitor cells (NSPCs), thereby further promoting endogenous nerve regeneration. NSPCs can always closely connect with vessels through the interaction of integrin α6ß1 and laminin; furthermore, under the support provided by the vascular niche and the chemotaxis of stromal cellderived factor (SDF-1), NSPCs can migrate from the subventricular zone (SVZ) to the periphery of infarction.

Patterned optogenetic modulation of neurovascular and metabolic signals.

The hemodynamic and metabolic response of the cortex depends spatially and temporally on the activity of multiple cell types. Optogenetics enables specific cell types to be modulated with high temporal precision and is therefore an emerging method for studying neurovascular and neurometabolic coupling. Going beyond temporal investigations, we developed a microprojection system to apply spatial photostimulus patterns in vivo. We monitored vascular and metabolic fluorescence signals after photostimulation in Thy1-channelrhodopsin-2 mice. Cerebral arteries increased in diameter rapidly after photostimulation, while nearby veins showed a slower smaller response. The amplitude of the arterial response was depended on the area of cortex stimulated. The fluorescence signal emitted at 450/100 nm and excited with ultraviolet is indicative of reduced nicotinamide adenine dinucleotide, an endogenous fluorescent enzyme involved in glycolysis and the citric acid cycle. This fluorescence signal decreased quickly and transiently after optogenetic stimulation, suggesting that glucose metabolism is tightly locked to optogenetic stimulation. To verify optogenetic stimulation of the cortex, we used a transparent substrate microelectrode array to map cortical potentials resulting from optogenetic stimulation. Spatial optogenetic stimulation is a new tool for studying neurovascular and neurometabolic coupling.

Neurovascular signaling in the brain and the pathological consequences of hypertension.

The execution and maintenance of all brain functions are dependent on a continuous flow of blood to meet the metabolic needs of the tissue. To ensure the delivery of resources required for neural processing and the maintenance of neural homeostasis, the cerebral vasculature is elaborately and extensively regulated by signaling from neurons, glia, interneurons, and perivascular nerves. Hypertension is associated with impaired neurovascular regulation of the cerebral circulation and culminates in neurodegeneration and cognitive dysfunction. Here, we review the physiological processes of neurovascular signaling in the brain and discuss mechanisms of hypertensive neurovascular dysfunction.

Migraine pathophysiology: anatomy of the trigeminovascular pathway and associated neurological symptoms, cortical spreading depression, sensitization, and modulation of pain.

Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex.

Sympathetic regulation of cerebral blood flow in humans: a review.

Cerebral blood flow (CBF) is regulated by vasomotor, chemical, metabolic, and neurogenic mechanisms. Even though the innervation of cerebral arteries is quite extensively described and reviewed in the literature, its role in regulation of CBF in humans remains controversial. We believe that insufficient attention has so far been focused on the potential role of the innervation of the cerebral vasculature in cerebral autoregulation in humans. We have performed an extensive search and selection of available literature on electrical, chemical, and surgical manipulations of the sympathetic innervation of cerebral arteries, and the effects of circulation sympathetically active agents on CBF. Studies on (surgical) ganglion block show a role of sympathetic tone in preventing increases in CBF in humans, which are consistent with the view based on animal studies. Both direct innervation of the cerebral arteries from cervical ganglia and stimulation of adrenergic receptors by circulating sympathomimetics prevent sudden increases of CBF associated with hypertension and hypercapnia. We postulate that under normal physiological conditions neurogenic control has little influence on cerebral autoregulation as other methods of control (vasomotor, chemical, and metabolic) are dominant. In severely challenging circumstances, such as delayed cerebral ischaemia after subarachnoid haemorrhage, these methods might be overwhelmed, increasing the relative importance of neurogenic, sympathetic control of CBF. This insight might lead to future therapeutic possibilities.

CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?

UNLABELLED: The neuropeptide calcitonin gene-related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor-like receptor (CLR). This associates with receptor activity-modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type-dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology. LINKED ARTICLES: This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

Perivascular expression and potent vasoconstrictor effect of dynorphin A in cerebral arteries.

BACKGROUND: Numerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of κ-opiate receptors in mediating the effect. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1-13) and DYN-A (1-17) but not DYN-A (1-8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K(+), were 115±6% and 104±10% in BAs and 113±3% and 125±9% in MCAs for 10 µM of DYN-A (1-13) and DYN-A (1-17), respectively. The vasoconstrictor effects of DYN-A (1-13) could be inhibited but not abolished by both the κ-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) DYN-A (2-13), which reportedly fails to activate κ-opiate receptors, induced vasoconstriction of 45±11% in BAs and 50±5% in MCAs at 10 µM, which effects were resistant to NORBI. CONCLUSION/SIGNIFICANCE: DYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by κ-opiate receptors and heterotrimeric G(i/o)-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of κ-opiate receptors.

Bimodal effects of fluoxetine on cerebral nitrergic neurogenic vasodilation in porcine large cerebral arteries.

Fluoxetine-induced relaxation of the smooth muscle of small cerebral arteries is thought beneficial in treating mental disorders. The present study was designed to examine effect of fluoxetine on neurogenic nitrergic vasodilation in large cerebral arteries, using in vitro tissue myography, techniques of electrophysiology, calcium imaging and biochemistry. In isolated porcine endothelium-denuded basilar arteries in the presence of U-46619-induced active muscle tone, fluoxetine in low concentration (<0.03 µM) significantly enhanced nicotine- and choline-induced relaxations. The vasorelaxation, however, was blocked by higher concentration of fluoxetine (>0.3 µM) with maximum inhibition at 3 µM. At this concentration, fluoxetine did not affect the basal tone or vasorelaxations induced by transmural nerve stimulation, sodium nitroprusside, or isoproterenol. Furthermore, fluoxetine exclusively blocked nicotine-induced inward currents and calcium influx in cultured neurons of rat superior cervical ganglion and Xenopus oocytes expressing human α7-, α3ß2-, or α4ß2-nicotinic acetylcholine receptors (nAChRs). In addition, fluoxetine at 0.03 µM and 3 µM significantly enhanced and blocked, respectively, nicotine-induced norepinephrine (NE) release from cerebral perivascular sympathetic nerves. These results indicate that fluoxetine via axo-axonal interaction mechanism exhibits bimodal effects on nAChR-mediated neurogenic nitrergic dilation of basilar arteries. Fluoxetine in high concentrations decreases while in low concentrations it increases neurogenic vasodilation. These results from in vitro experimentation suggest that optimal concentrations of fluoxetine which increase or minimally affect neurogenic vasodilation indicative of regional cerebral blood flow may be important consideration in treating mental disorders.

Nitrergic nerves derived from the pterygopalatine ganglion innervate arteries irrigating the cerebrum but not the cerebellum and brain stem in monkeys.

The functional roles of the nitrergic nerves innervating the monkey cerebral artery were evaluated in a tension-response study examining isolated arteries in vitro and cerebral angiography in vivo. Nicotine produced relaxation of arteries by stimulation of nerve terminals innervating isolated monkey arteries irrigating the cerebrum, cerebellum and brain stem. Relaxation of arteries induced by nicotine was abolished by treatment with N(G)-nitro-L-arginine, a nitric oxide synthase inhibitor, and was restored by addition of L-arginine. Cerebral angiography showed that electrical stimulation of the unilateral greater petrosal nerve, which connects to the pterygopalatine ganglion via the parasympathetic ganglion synapse, produced vasodilatation of the anterior, middle and posterior cerebral arteries in the stimulated side. However, stimulation failed to produce vasodilatation of the superior and anterior-inferior cerebellar arteries and the basilar artery in anesthetized monkeys. Therefore, nitrergic nerves derived from the pterygopalatine ganglion appear to regulate cerebral vasomotor function. In contrast, circulation in the cerebellum and brain stem might be regulated by nitrergic nerves originating not from the pterygopalatine ganglion, but rather from an unknown ganglion (or ganglia).

Distribution of H2S synthesis enzymes in the walls of cerebral arteries in rats.

The distribution of two enzymes involved in H(2)S synthesis, cystationine ß-synthase (CBS) and cystationine γ-liase (CSE), was studied in the walls of the internal carotid artery, order I-V branches of the middle cerebral artery basin, and intracerebral vessels of adult Wistar rats. Immunohistochemical staining showed the presence of CBS in the endothelium of small pial arteries (order IV-V branches) and intracerebral arterioles and in the capillary walls, neurons, and vascular nerves. As for CSE, in the internal carotid artery and large (order I-II) pial branches it was found mainly in the tunica media myocytes, in order III-IV vessels in myocytes and endothelium, and in smaller pial and intracerebral vessels in the endothelium. Along with enzyme-positive vessels, many pial and intracerebral arteries contained no these enzymes in the walls.

The effect of degenerated neuron density of petrosal ganglion on the development of blood pressure variabilities after subarachnoid hemorrhage in a rabbit model: an experimental study.

AIM: The aim of this study was to determine the relationship between ischemic neurodegeneration, of the petrosal ganglion of the glossopharyngeal nerve, and BP fluctuations, after subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Twenty-four rabbits had their blood pressure and heart rhythms studied daily over 20 days. Then, the histopathology of the petrosal ganglion was examined in all animals. Normal and apoptotic neuron density of the petrosal ganglion and blood pressure values were compared statistically. RESULTS: Mean total volume of the petrosal ganglia was calculated as 0.9 ± 0.34/mm3. BP level of control group was 96.1 ± 2.1 mmHg; 116.5 ± 4 mmHg of mild hypertension (HT) group and 128.1 ± 3.6mmHg in the severe HT group. When the groups were compared to each other they were significantly different. The level of normal-apoptotic neuron in control group was 11,240 ± 802/mm³ -40 ± 6.3/mm³; 9730 ± 148.7/mm³ - 1560 ± 256.2/mm³ in the mild HT group and 6870 ± 378.8/mm³-4240 ± 628.2/mm³ in the severe HT group. When the groups were compared to each other there was significantly difference. CONCLUSION: Blood pressure variability observed in this study may be explained by ischemic neurodegeneration of petrosal ganglia caused by SAH. The results of this study suggest that petrosal ganglion ischemia has potential implications for the development of hypertension. These findings suggest that new treatment strategies should be considered for the treatment of SAH.

Focus on the management of thunderclap headache: from nosography to treatment.

Thunderclap headache (TCH) is an excruciating headache characterized by a very sudden onset. Recognition and accurate diagnosis of TCH are important in order to rule out the various, serious underlying brain disorders that, in a high percentage of cases, are the real cause of the headache. Primary TCH, which may recur intermittently and generally has a spontaneous, benign evolution, can thus be diagnosed only when all other potential underlying causes have been excluded through accurate diagnostic work up. In this review, we focus on the management of TCH, paying particular attention to the diagnostic work up and treatment of the condition.

Cerebral vasoreactivity during hypercapnia is reset by augmented sympathetic influence.

Sympathetic nerve activity influences cerebral blood flow, but it is unknown whether augmented sympathetic nerve activity resets cerebral vasoreactivity to hypercapnia. This study tested the hypothesis that cerebral vasodilation during hypercapnia is restrained by lower-body negative pressure (LBNP)-stimulated sympathoexcitation. Cerebral hemodynamic responses were assessed in nine healthy volunteers [age 25 yr (SD 3)] during rebreathing-induced increases in partial pressure of end-tidal CO(2) (Pet(CO(2))) at rest and during LBNP. Cerebral hemodynamic responses were determined by changes in flow velocity of middle cerebral artery (MCAV) using transcranial Doppler sonography and in regional cerebral tissue oxygenation (ScO(2)) using near-infrared spectroscopy. Pet(CO(2)) values during rebreathing were similarly increased from 41.9 to 56.5 mmHg at rest and from 40.7 to 56.0 mmHg during LBNP of -15 Torr. However, the rates of increases in MCAV and in ScO(2) per unit increase in Pet(CO(2)) (i.e., the slopes of MCAV/Pet(CO(2)) and ScO(2)/Pet(CO(2))) were significantly (P ≤0.05) decreased from 2.62 ± 0.16 cm·s(-1)·mmHg(-1) and 0.89 ± 0.10%/mmHg at rest to 1.68 ± 0.18 cm·s(-1)·mmHg(-1) and 0.63 ± 0.07%/mmHg during LBNP. In conclusion, the sensitivity of cerebral vasoreactivity to hypercapnia, in terms of the rate of increases in MCAV and in ScO(2), is diminished by LBNP-stimulated sympathoexcitation.

Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system.

Clinical and genetic studies have suggested a role for voltage gated calcium channels (VGCCs) in the pathogenesis of migraine. Release of calcitonin gene-related peptide (CGRP) from trigeminal neurons has also been implicated in migraine. The VGCCs are located presynaptically on neurons and are involved in the release of these peptides to different stimuli. We have examined the presence and importance of VGCCs in controlling the CGRP release from rat dura mater, freshly isolated trigeminal ganglion (TG) and trigeminal nucleus caudalis (TNC). Each of the four VGCCs, P/Q-, N-, and L- and T-type are abundantly found in TG and TNC relative to the dura mater and each mediates a significant fraction of high potassium concentration induced CGRP release. In dura mater, blockade of P/Q-, N- and L-type VGCCs by ω-agatoxin TK, ω-conotoxin GVIA and nimodipine at 1 µM respectively, significantly decreased the potassium induced CGRP release. In the absence of calcium ions (Ca2+) and in the presence of a cocktail of blockers, the stimulated CGRP release from dura mater was reduced almost to the same level as basal CGRP release. In the TG ω-conotoxin GVIA inhibited the potassium induced CGRP release significantly. In the absence of Ca2+ and in the presence of a cocktail of blockers the stimulated CGRP release was significantly reduced. In the TNC only the cocktail of blockers and the absence of Ca2+ could reduce the potassium induced release significantly. These results suggest that depolarization by high potassium releases CGRP, and the release is regulated by Ca2+ ions and voltage-gated calcium channels.

[Receptor system of brain vessels in arterial hypertension].

We conducted a post-mortem study of the receptor system of brain vessels in patients with arterial hypertension (AG), stages I-III, and healthy people using impregnation and a method of measuring NADPH-diaphorase. The receptor system of arterial wall is represented by treelike and glomerular structures with moderate enzyme activity. Reactive and destructive disturbances of the receptor system that were distinctly seen on histochemical preparations were found in brain arteries of AG patients. The intensity of changes in the nervous apparatus of brain vessels was closely related to the artery caliber, their localization, disease duration and severity, with the most early and deep changes in the afferent fibers and receptors of the pia mater arteries. In intracerebral arteries, reactive changes in receptor structures were found in long-term hypertension and destructive changes were found in AG, stages II-III.