scholarly journals Delayed astrocytic contact with cerebral blood vessels in FGF-2 deficient mice does not compromise permeability properties at the developing blood-brain barrier

2016 ◽  
Vol 76 (11) ◽  
pp. 1201-1212 ◽  
Author(s):  
Norman R. Saunders ◽  
Katarzyna M. Dziegielewska ◽  
Klaus Unsicker ◽  
C. Joakim Ek
Keyword(s):  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Cerebral Blood Vessels ◽  
Blood Brain ◽  
Deficient Mice

scholarly journals Size-selective loosening of the blood-brain barrier in claudin-5–deficient mice

2003 ◽  
Vol 161 (3) ◽  
pp. 653-660 ◽  
Author(s):  
Takehiro Nitta ◽  
Masaki Hata ◽  
Shimpei Gotoh ◽  
Yoshiteru Seo ◽  
Hiroyuki Sasaki ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Blood Vessels ◽  
Tight Junctions ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blood Brain ◽  
The Central Nervous System ◽  
Deficient Mice

Tight junctions are well-developed between adjacent endothelial cells of blood vessels in the central nervous system, and play a central role in establishing the blood-brain barrier (BBB). Claudin-5 is a major cell adhesion molecule of tight junctions in brain endothelial cells. To examine its possible involvement in the BBB, claudin-5–deficient mice were generated. In the brains of these mice, the development and morphology of blood vessels were not altered, showing no bleeding or edema. However, tracer experiments and magnetic resonance imaging revealed that in these mice, the BBB against small molecules (<800 D), but not larger molecules, was selectively affected. This unexpected finding (i.e., the size-selective loosening of the BBB) not only provides new insight into the basic molecular physiology of BBB but also opens a new way to deliver potential drugs across the BBB into the central nervous system.

Effects of endothelin and vasopressin on cerebral blood vessels

1989 ◽  
Vol 257 (3) ◽  
pp. H799-H803 ◽  
Author(s):  
F. M. Faraci
Keyword(s):  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Basilar Artery ◽  
Brain Barrier ◽  
Fluorescein Sodium ◽  
Cerebral Blood Vessels ◽  
Blood Brain ◽  
Pial Arterioles ◽  
High Doses ◽  
The Brain

Endothelin is a recently described peptide which has been suggested to be one type of endothelium-derived contracting factor. The goals of the present study were to examine the effects of endothelin and vasopressin on diameter of cerebral vessels and on permeability of the blood-brain barrier to fluorescein sodium (mol wt of 376). In anesthetized rats, topical suffusion of arginine vasopressin (10(-10) to 10(-7) M) decreased the diameter of pial arterioles, with a reduction of 27 +/- 1% at 10(-7) M in cerebrum and 35 +/- 2% at 10(-8) M for the basilar artery. A low concentration of endothelin (10(-10) M) produced modest (5 +/- 1%) dilatation of pial arterioles. Higher concentrations of endothelin (10(-8) and 10(-7) M) constricted pial arterioles with a reduction in diameter of 22 +/- 5% at 10(-7) M. Dilatation to endothelin was not observed in the basilar artery. The basilar artery constricted to lower doses of vasopressin than endothelin, but vasoconstriction to 10(-7) M endothelin (56 +/- 4%) was greater (P less than 0.05) than that for the same dose of vasopressin. Permeability of the blood-brain barrier to fluorescein sodium was not increased by vasopressin or endothelin. Thus 1) vasopressin produces constriction of brain blood vessels; 2) endothelin produces dilatation of pial arterioles at low doses but constriction at high doses; 3) constrictor responses to both peptides appear to be greater in the brain stem than in the cerebrum; and 4) vasopressin and endothelin do not increase permeability of the blood-brain barrier.

scholarly journals PATH-04. THE BLOOD-BRAIN BARRIER IN DIFFUSE MIDLINE GLIOMA AND ITS IMPLICATIONS FOR DRUG DELIVERY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii164-ii164
Author(s):  
Rianne Haumann ◽  
Fatma El-Khouly ◽  
Marjolein Breur ◽  
Sophie Veldhuijzen van Zanten ◽  
Gertjan Kaspers ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Vascular Density ◽  
Zonula Occludens ◽  
Blood Brain ◽  
Zonula Occludens 1 ◽  
End Stage ◽  
Diffuse Midline Glioma

Abstract INTRODUCTION Chemotherapy has been unsuccessful for pediatric diffuse midline glioma (DMG) most likely due to an intact blood-brain barrier (BBB). However, the BBB has not been characterized in DMG and therefore its implications for drug delivery are unknown. In this study we characterized the BBB in DMG patients and compared this to healthy controls. METHODS End-stage DMG pontine samples (n=5) were obtained from the VUmc diffuse intrinsic pontine glioma (DIPG) autopsy study and age-matched healthy pontine samples (n=22) were obtained from the NIH NeuroBioBank. Tissues were stained for BBB markers claudin-5, zonula occludens-1, laminin, and PDGFRβ. Claudin-5 stains were used to determine vascular density and diameter. RESULTS In DMG, expression of claudin-5 was reduced and dislocated to the abluminal side of endothelial cells. In addition, the expression of zonula occludens-1 was reduced. The basement membrane protein laminin expression was reduced at the glia limitans in both pre-existent vessels and neovascular proliferation. PDGFRβ expression was not observed in DMG but was present in healthy pons. Furthermore, the number of blood vessels in DMG was significantly (P< 0.01) reduced (13.9 ± 11.8/mm2) compared to healthy pons (26.3 ± 14.2/mm2). Markedly, the number of small blood vessels (< 10µm) was significantly lower (P< 0.01) while larger blood vessels (> 10µm) were not significantly different (P= 0.223). The mean vascular diameter was larger for DMG 9.3 ± 9.9µm compared to 7.7 ± 9.0µm for healthy pons (P= 0.016). CONCLUSION Both the BBB and the vasculature are altered at end-stage DMG. The reduced vascular density might have implications for several drug delivery methods such as focused ultrasound and convection enhanced delivery that are being explored for the treatment of DMG. The functional effects of the structurally altered BBB remain unknown and further research is needed to evaluate the BBB integrity at end-stage DMG

scholarly journals Encephalitic Alphaviruses Exploit Caveola-Mediated Transcytosis at the Blood-Brain Barrier for Central Nervous System Entry

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hamid Salimi ◽  
Matthew D. Cain ◽  
Xiaoping Jiang ◽  
Robyn A. Roth ◽  
Wandy L. Beatty ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Endothelial Cells ◽  
Nervous System ◽  
Viral Replication ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Type I ◽  
Brain Endothelial Cells ◽  
Blood Brain ◽  
Deficient Mice

ABSTRACT Venezuelan and western equine encephalitis viruses (VEEV and WEEV, respectively) invade the central nervous system (CNS) early during infection, via neuronal and hematogenous routes. While viral replication mediates host shutoff, including expression of type I interferons (IFN), few studies have addressed how alphaviruses gain access to the CNS during established infection or the mechanisms of viral crossing at the blood-brain barrier (BBB). Here, we show that hematogenous dissemination of VEEV and WEEV into the CNS occurs via caveolin-1 (Cav-1)-mediated transcytosis (Cav-MT) across an intact BBB, which is impeded by IFN and inhibitors of RhoA GTPase. Use of reporter and nonreplicative strains also demonstrates that IFN signaling mediates viral restriction within cells comprising the neurovascular unit (NVU), differentially rendering brain endothelial cells, pericytes, and astrocytes permissive to viral replication. Transmission and immunoelectron microscopy revealed early events in virus internalization and Cav-1 association within brain endothelial cells. Cav-1-deficient mice exhibit diminished CNS VEEV and WEEV titers during early infection, whereas viral burdens in peripheral tissues remained unchanged. Our findings show that alphaviruses exploit Cav-MT to enter the CNS and that IFN differentially restricts this process at the BBB. IMPORTANCE VEEV, WEEV, and eastern equine encephalitis virus (EEEV) are emerging infectious diseases in the Americas, and they have caused several major outbreaks in the human and horse population during the past few decades. Shortly after infection, these viruses can infect the CNS, resulting in severe long-term neurological deficits or death. Neuroinvasion has been associated with virus entry into the CNS directly from the bloodstream; however, the underlying molecular mechanisms have remained largely unknown. Here, we demonstrate that following peripheral infection alphavirus augments vesicular formation/trafficking at the BBB and utilizes Cav-MT to cross an intact BBB, a process regulated by activators of Rho GTPases within brain endothelium. In vivo examination of early viral entry in Cav-1-deficient mice revealed significantly lower viral burdens in the brain than in similarly infected wild-type animals. These studies identify a potentially targetable pathway to limit neuroinvasion by alphaviruses.

scholarly journals Immunolocalization of Heat Shock Protein after Fluid Percussive Brain Injury and Relationship to Breakdown of the Blood-Brain Barrier

1993 ◽  
Vol 13 (1) ◽  
pp. 116-124 ◽  
Author(s):  
Hirokazu Tanno ◽  
Russ P. Nockels ◽  
Lawrence H. Pitts ◽  
Linda J. Noble
Keyword(s):  
Brain Injury ◽  
Head Injury ◽  
Blood Vessels ◽  
Blood Brain Barrier ◽  
Time Course ◽  
Cortical Layer ◽  
Brain Barrier ◽  
Impact Site ◽  
Blood Brain ◽  
The Impact

We have previously developed a model of mild, lateral fluid percussive head injury in the rat and demonstrated that although this injury produced minimal hemorrhage, breakdown of the blood–brain barrier was a prominent feature. The relationship between posttraumatic blood–brain barrier disruption and cellular injury is unclear. In the present study we examined the distribution and time course of expression of the stress protein HSP72 after brain injury and compared these findings with the known pattern of breakdown of the blood–brain barrier after a similar injury. Rats were subjected to a lateral fluid percussive brain injury (4.8–5.2 atm, 20 ms) and killed at 1, 3, and 6 h and 1,3, and 7 days after injury. HSP72-like immunoreactivity was evaluated in sections of brain at the light-microscopic level. The earliest expression of HSP72 occurred at 3 h postinjury and was restricted to neurons and glia in the cortex surrounding a necrotic area at the impact site. By 6 h, light immunostaining was also noted in the pia-arachnoid adjacent to the impact site and in certain blood vessels that coursed through the area of necrosis. Maximal immunostaining was observed by 24 h postinjury, and was primarily associated with the cortex immediately adjacent to the region of necrosis at the impact site. This region consisted of darkly immunostained neurons, glia, and blood vessels. Immunostaining within the region of necrosis was restricted to blood vessels. HSP72-like immunoreactivity was also noted in a limited number of neurons and glia in other brain regions, including the parasagittal cortex, deep cortical layer VI, and CA3 in the posterior hippocampus. Immunoreactive cells in these areas were not apparent until 24 h postinjury. By 7 days postinjury, HSP72-like immunoreactivity was minimal or absent in these injured brains and notable cell loss was apparent only in the impact site. This study demonstrates an early and pronounced expression of HSP72 at the impact site and a more delayed and less prominent expression of this protein in other regions of the brain. These findings parallel the temporal and regional pattern of breakdown of the blood–brain barrier after a similar head injury.

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