Quantifying neurovascular canal branching patterns reveals a shared crocodylian arrangement.

Highly branched dendritic structures are common in nature and often difficult to quantify and therefore compare. Cranial neurovascular canals, examples of such structures, are osteological correlates for somatosensory systems and have been explored only qualitatively. Adaptations of traditional stream-ordering methods are applied to representative structures derived from computed tomography-scan data. Applying these methods to crocodylian taxa, this clade demonstrates a shared branching pattern and exemplifies the comparative utility of these methods. Additionally, this pattern corresponds with current understanding of crocodylian sensory abilities and behaviors. The method is applicable to many taxa and anatomical structures and provides evidence for morphology-based hypotheses of sensory and physiological evolution.

Constitutive Androstane Receptor: A Peripheral and a Neurovascular Stress or Environmental Sensor.

Xenobiotic nuclear receptors (NR) are intracellular players involved in an increasing number of physiological processes. Examined and characterized in peripheral organs where they govern metabolic, transport and detoxification mechanisms, accumulating data suggest a functional expression of specific NR at the neurovascular unit (NVU). Here, we focus on the Constitutive Androstane Receptor (CAR), expressed in detoxifying organs such as the liver, intestines and kidneys. By direct and indirect activation, CAR is implicated in hepatic detoxification of xenobiotics, environmental contaminants, and endogenous molecules (bilirubin, bile acids). Importantly, CAR participates in physiological stress adaptation responses, hormonal and energy homeostasis due to glucose and lipid sensing. We next analyze the emerging evidence supporting a role of CAR in NVU cells including the blood-brain barrier (BBB), a key vascular interface regulating communications between the brain and the periphery. We address the emerging concept of how CAR may regulate specific P450 cytochromes at the NVU and the associated relevance to brain diseases. A clear understanding of how CAR engages during pathological conditions could enable new mechanistic, and perhaps pharmacological, entry-points within a peripheral-brain axis.

The Role of Neurovascular System in Neurodegenerative Diseases.

The neurovascular system (NVS), which consisted of neurons, glia, and vascular cells, is a functional and structural unit of the brain. The NVS regulates blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), thereby maintaining the brain's microenvironment for normal functioning, neuronal survival, and information processing. Recent studies have highlighted the role of vascular dysfunction in several neurodegenerative diseases. This is not unexpected since both nervous and vascular systems are functionally interdependent and show close anatomical apposition, as well as similar molecular pathways. However, despite extensive research, the precise mechanism by which neurovascular dysfunction contributes to neurodegeneration remains incomplete. Therefore, understanding the mechanisms of neurovascular dysfunction in disease conditions may allow us to develop potent and effective therapies for prevention and treatment of neurodegenerative diseases. This review article summarizes the current research in the context of neurovascular signaling associated with neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We also discuss the potential implication of neurovascular factor as a novel therapeutic target and prognostic marker in patients with neurodegenerative conditions. Graphical Abstract.

Neuroanatomy of the middle cerebral artery: implications for thrombectomy.

Our perspective on anatomy frequently depends on how this anatomy is utilized in clinical practice, and by which methods knowledge is acquired. The thrombectomy revolution, of which the middle cerebral artery (MCA) is the most common target, is an example of a clinical paradigm shift with a unique perspective on cerebrovascular anatomy. This article reviews important features of MCA anatomy in the context of thrombectomy. Recognizing that variation, frequently explained by evolutionary concepts, is the rule when it comes to branching pattern, vessel morphology, territory, or collateral potential is key to successful thrombectomy strategy.

[Bioinks and in vitro neurovascular unit production - New prospects in Alzheimer's disease research].

Neurovascular dysfunction is a central process in the pathogenesis of the stroke and most neurodegenerative diseases, including Alzheimer's disease. The multi-cell neurovascular unit (NVU) combines the components of the neural, vascular and extracellular matrix (ECM) into an important interface whose proper function is critical to maintaining brain health. Tissue engineering now offers new tools and information to promote understanding of NVU's operation. A promising area for the development of NVU models is their bio-production through 3D bio-printing to produce a multi-layered NVU in which the contribution of the different cell types to neurovascular function and dysfunction can be studied at molecular and cellular levels. Nerve and vascular cells are encapsulated in a construct suitable for their viability and growth. This construct, called "bioink", is a pre-gelled biomaterial, usually with encapsulated cells, which can be bio-printed and gelled to successfully form a solid construct. Bio-printing allows accurate placement of the neural and vascular cells to form appropriate interactions mimicking the in vivo state. Individual NVU cell types interact with the other cellular components of NVU through biochemical and physical markers, with direct and indirect interactions between neural and vascular components. The cell line sources, either derived from AD patients or healthy individuals, can be developed with the IPSCs technology. IPSCs can be obtained by different somatic cells via reprogramming strategies and further on differentiated into various cell lines that can be used to model disease, to discover new drugs and to treat cell replacement. Last but not least, the availability of 3D NVU models can also facilitate screening of drugs to correct neural dysfunction due to stroke, Alzheimer's disease and other dementia.

Innate Immunity Cells and the Neurovascular Unit.

Recent studies have clarified many still unknown aspects related to innate immunity and the blood-brain barrier relationship. They have also confirmed the close links between effector immune system cells, such as granulocytes, macrophages, microglia, natural killer cells and mast cells, and barrier functionality. The latter, in turn, is able to influence not only the entry of the cells of the immune system into the nervous tissue, but also their own activation. Interestingly, these two components and their interactions play a role of great importance not only in infectious diseases, but in almost all the pathologies of the central nervous system. In this paper, we review the main aspects in the field of vascular diseases (cerebral ischemia), of primitive and secondary neoplasms of Central Nervous System CNS, of CNS infectious diseases, of most common neurodegenerative diseases, in epilepsy and in demyelinating diseases (multiple sclerosis). Neuroinflammation phenomena are constantly present in all diseases; in every different pathological state, a variety of innate immunity cells responds to specific stimuli, differentiating their action, which can influence the blood-brain barrier permeability. This, in turn, undergoes anatomical and functional modifications, allowing the stabilization or the progression of the pathological processes.

The plantaris muscle - rare relations to the neurovascular bundle in the popliteal fossa.

The plantaris muscle is characterised by morphological variability, both for origin and insertion, and may sometimes be absent. Its strength allows the ligament to be used for reconstruction of other tendons and ligaments. This report presents the rare placements and course of the plantaris muscle in relation to the neurovascular bundle. In this case, the hypertrophy of this muscle might cause pressure on the tibial nerve and produce symptoms similar to sciatica.

Effects of hemodialysis on intraneural blood flow in end-stage kidney disease.

INTRODUCTION: We quantified intraneural blood flow (INBF) in 18 patients with end-stage kidney disease (ESKD) and examined its relationship with nerve size, neuropathy severity, and nerve excitability parameters. METHODS: Sonographic measurements of the median nerve were performed at the same site before and after hemodialysis. INBF was quantified by analyzing power Doppler sonograms to obtain the vessel score (VSc) and maximum perfusion intensity (MPI). Corresponding median motor nerve excitability studies were performed. Neuropathy severity was assessed using Total Neuropathy Score. RESULTS: A total of 39% of ESKD patients had detectable INBF compared with none in the control group (P < 0.0001). Patients with detectable INBF had larger nerves and more severe neuropathy (P < 0.01). INBF parameters were significantly reduced after a session of dialysis (VSc: P < 0.01; MPI: P < 0.01). A significant relationship was found between interdialytic change in INBF and changes in nerve excitability. CONCLUSIONS: Increased INBF is a potential marker for neuropathy severity in ESKD patients. Muscle Nerve 57: 287-293, 2018.

JunB regulates angiogenesis and neurovascular parallel alignment in mouse embryonic skin.

Blood vessels and nerve fibers are often closely arranged in parallel throughout the body. Therefore, neurovascular interactions have been suggested to be important for the development of vascular networks. However, the molecular mechanisms and genes regulating this process remain unclear. In the present study, we investigated the genes that are activated in endothelial cells (ECs) following interactions with neurons during vascular development. Microarray analyses of human primary microvascular ECs co-cultured with mouse primary dorsal root ganglion cells showed that JunB is strongly upregulated in ECs by neurovascular interactions. Furthermore, the forced expression of JunB in ECs stimulated a tip-like cell formation and angiogenesis in vitro and induced vascular endothelial growth factor A (VEGFA) and the pro-angiogenic integrin subunit ITGB3 expression. Moreover, in vivo knockdown of JunB in ECs from developing mouse limb skin considerably decreased the parallel alignments of blood vessels and nerve fibers. Taken together, the present data demonstrates for the first time that JunB plays an important role in the formation of embryonic vascular networks. These results contribute to the molecular understanding of neurovascular interactions during embryonic vascular development.

Knockdown of CXCL14 disrupts neurovascular patterning during ocular development.

The C-X-C motif ligand 14 (CXCL14) is a recently discovered chemokine that is highly conserved in vertebrates and expressed in various embryonic and adult tissues. CXCL14 signaling has been implicated to function as an antiangiogenic and anticancer agent in adults. However, its function during development is unknown. We previously identified novel expression of CXCL14 mRNA in various ocular tissues during development. Here, we show that CXCL14 protein is expressed in the anterior eye at a critical time during neurovascular development and in the retina during neurogenesis. We report that RCAS-mediated knockdown of CXCL14 causes severe neural defects in the eye including precocious and excessive innervation of the cornea and iris. Absence of CXCL14 results in the malformation of the neural retina and misprojection of the retinal ganglion neurons. The ocular neural defects may be due to loss of CXCL12 modulation since recombinant CXCL14 diminishes CXCL12-induced axon growth in vitro. Furthermore, we show that knockdown of CXCL14 causes neovascularization of the cornea. Altogether, our results show for the first time that CXCL14 plays a critical role in modulating neurogenesis and inhibiting ectopic vascularization of the cornea during ocular development.

Vasoregression: A Shared Vascular Pathology Underlying Macrovascular And Microvascular Pathologies?

Vasoregression is a common phenomenon underlying physiological vessel development as well as pathological microvascular diseases leading to peripheral neuropathy, nephropathy, and vascular oculopathies. In this review, we describe the hallmarks and pathways of vasoregression. We argue here that there is a parallel between characteristic features of vasoregression in the ocular microvessels and atherosclerosis in the larger vessels. Shared molecular pathways and molecular effectors in the two conditions are outlined, thus highlighting the possible systemic causes of local vascular diseases. Our review gives us a system-wide insight into factors leading to multiple synchronous vascular diseases. Because shared molecular pathways might usefully address the diagnostic and therapeutic needs of multiple common complex diseases, the literature analysis presented here is of broad interest to readership in integrative biology, rational drug development and systems medicine.

Preliminary methods for wearable neuro-vascular assessment with non-invasive, active sensing.

In this study, a non-invasive and active sensing scheme that is ultimately aimed to be integrated in a wearable system for neuro-vascular health assessment is presented with preliminary results. With this system, vascular tone is modulated by local heating and cooling of the palm, and the resulting changes in local hemodynamics are monitored via impedance plethysmography (IPG) and photoplethysmography (PPG) sensors interfaced with custom analog electronics. Proof-of-concept measurements were conducted on three subjects using hot packs/ice bags to modulate the palmar skin temperature. From ensemble averaged and smoothed versions of pulsatile IPG and PPG signals, the effects of local changes in skin temperature on a series of parameters associated with neuro-vascular mechanisms (heart rate, blood volume, blood flow rate, blood volume pulse inflection point area ratio, and local pulse transit time) have been observed. The promising experimental results suggest that, with different active temperature modulation schemes (consisting of heating/cooling cycles covering different temperature ranges at different rates), it would be possible to enhance the depth and specificity of the information associated with neuro-vascular health by using biosensors that can fit inside a wearable device (such as a sleeve). This study sets the foundation for future studies on designing and testing such a wearable neuro-vascular health assessment system employing active sensing.

Neurovascular coupling and the influence of luminal agonists via the endothelium.

A numerical model of neurovascular coupling (NVC) is presented based on neuronal activity coupled to vasodilation/contraction models via the astrocytic mediated perivascular K(+) and the smooth muscle cell Ca(2+) pathway. Luminal agonists acting on P2Y receptors on the endothelial cell surface provide a flux of IP3 into the endothelial cytosol. This concentration of IP3 is transported via gap junctions between endothelial and smooth muscle cells providing a source of sacroplasmic derived Ca(2+) in the smooth muscle cell. The model is able to relate a neuronal input signal to the corresponding vessel reaction. Results indicate that blood flow mediated IP3 production via the agonist ATP has a substantial effect on the contraction/dilation dynamics of the SMC. The resulting variation in cytosolic Ca(2+) can enhance and inhibit the flow of blood to the cortical tissue. IP3 coupling between endothelial and smooth muscle cells seems to be important in the dynamics of the smooth muscle cell. The VOCC channels are, due to the hyperpolarisation from K(+) SMC efflux, almost entirely closed and do not seem to play a significant role during neuronal activity. The current model shows that astrocytic Ca(2+) is not necessary for neurovascular coupling to occur in contrast to a number of experiments outlining the importance of astrocytic Ca(2+) in NVC, however this Ca(2+) pathway is not the only one mediating NVC. Importantly agonists in flowing blood have a significant influence on the endothelial and smooth muscle cell dynamics.

The key role of transient receptor potential melastatin-2 channels in amyloid-ß-induced neurovascular dysfunction.

Alzheimer's dementia is a devastating and incurable disease afflicting over 35 million people worldwide. Amyloid-ß (Aß), a key pathogenic factor in this disease, has potent cerebrovascular effects that contribute to brain dysfunction underlying dementia by limiting the delivery of oxygen and glucose to the working brain. However, the downstream pathways responsible for the vascular alterations remain unclear. Here we report that the cerebrovascular dysfunction induced by Aß is mediated by DNA damage caused by vascular oxidative-nitrosative stress in cerebral endothelial cells, which, in turn, activates the DNA repair enzyme poly(ADP)-ribose polymerase. The resulting increase in ADP ribose opens transient receptor potential melastatin-2 (TRPM2) channels in endothelial cells leading to intracellular Ca(2+) overload and endothelial dysfunction. The findings provide evidence for a previously unrecognized mechanism by which Aß impairs neurovascular regulation and suggest that TRPM2 channels are a potential therapeutic target to counteract cerebrovascular dysfunction in Alzheimer's dementia and related pathologies.

Patient body weight-tailored contrast medium injection protocol for the craniocervical vessels: a prospective computed tomography study.

OBJECTIVES: To evaluate body weight-tailored contrast medium (CM) administration for computed tomography angiography (CTA) of the craniocervical vessels. METHODS: Institutional review board approval was obtained, and all patients gave written informed consent. Sixty patients were consecutively assigned to one of three dose groups (20 patients per group) with CM doses of Visipaque 270® (iodixanol 270 mg/ml) tailored to body weight at doses of 1.5, 1.0, or 0.5 ml/kg. Region-of-interest (ROI) analysis of maximum enhancement (ME) was conducted, and signal-to-noise-ratios (SNR) and contrast-to-noise-ratios (CNR) were calculated. Retrospective comparison was performed with three matched control groups examined with a standard CM dose (80 ml of Visipaque 270®). Image quality was rated by two neuroradiologists blinded to the CM dose used. Interrater reliability was calculated using kappa statistics. RESULTS: Body weight/BMI and ME were inversely correlated in the three control groups receiving the standard dose (r = -0.544/-0.597/-0.542/r = -0.358/r = -0.424/r = -0.280). Compared to standard dose, 1.5 ml/kg produced higher ME, SNR, and CNR in the anterior circulation (p≤0.038), 1.0 ml/kg had higher ME in cervical and medium-sized cerebral arteries (p≤0.034), and 0.5 ml/kg had lower ME, SNR and CNR for medium-sized cerebral arteries (p≤0.049). ME, SNR, and CNR were the same for 1.5 ml/kg and 1.0 ml/kg (p≥0.24), and both had higher values compared to 0.5 ml/kg (p≤0.043/p≤0.028). In patients with BMI>25, 1.5 ml/kg and 1.0 ml/kg produced higher ME than standard dose (p<0.001/p = 0.008), but ME in patients with BMI>25 did not differ between group 1 and group 2 (p = 0.673). In patients with BMI≤25, 1.5 ml/kg and 1.0 ml/kg produced ME comparable to standard dose (p = 0.132/p = 0.403). Regardless of patient weight, 0.5 ml/kg yielded lower ME than standard dose (p = 0.019/0.002). CONCLUSIONS: Craniocervical CTA with a body weight-tailored CM dose of 1.0 ml/kg (270 mg iodine/ml) reduces iodine load in patients weighing <80 kg while producing ME similar to standard dose and improves ME in patients with BMI>25.

ALS and oxidative stress: the neurovascular scenario.

Oxidative stress and angiogenic factors have been placed as the prime focus of scientific investigations after an establishment of link between vascular endothelial growth factor promoter (VEGF), hypoxia, and amyotrophic lateral sclerosis (ALS) pathogenesis. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter and mutant superoxide dismutase 1 (SOD1) which are characterised by atrophy and muscle weakness resulted in phenotype resembling human ALS in mice. This results in lower motor neurodegeneration thus establishing an important link between motor neuron degeneration, vasculature, and angiogenic molecules. In this review, we have presented human, animal, and in vitro studies which suggest that molecules like VEGF have a therapeutic, diagnostic, and prognostic potential in ALS. Involvement of vascular growth factors and hypoxia response elements also highlights the converging role of oxidative stress and neurovascular network for understanding and treatment of various neurodegenerative disorders like ALS.

Neurovascular function and sudorimetry in health and disease.

In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians.