Molecular Changes Associated with the Protective Effects of Angiopoietin-1 During Blood-Brain Barrier Breakdown Post-Injury

Nag, Sukriti; Manias, Janet L.; Kapadia, Anish; Stewart, Duncan J.

doi:10.1007/s12035-016-9973-4

Cited by 16 publications

(15 citation statements)

References 58 publications

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“…± 0.3) mm and extended into cortical layer 4 as a shallow bowl-shaped lesion. Morphological changes in the cortical cold lesions were similar to our previous observations, including the time course of BBB breakdown, angiogenesis, and the inflammatory cell responses [9,27,29,30,31]. On day 0.5, the lesion area showed coagulative necrosis of the neuropil associated with neuronal loss and residual neurons in this area showed varying degrees of degeneration (Figure 1d).…”

Section: Resultssupporting

confidence: 86%

“…The cold-injury model has been utilized extensively to study BBB breakdown, the initiating factor in vasogenic edema using tracers such as Evans blue [32] and horseradish peroxidase (HRP) [27,30] and also by the immunolocalization of extravasated circulating proteins such as serum proteins [27], fibrinogen [33], and fibronectin [8,29,30] through vessels into the surrounding brain. Since all vessels within the lesion do not show BBB breakdown, immunofluorescence allows the identification of vessels leaking proteins while dual labeling allows the localization of a protein of interest in the endothelium of vessels leaking proteins in the same animal.…”

Section: Discussionmentioning

confidence: 99%

“…These criteria were met by the rat cortical cold-injury model which was developed by Igor Klatzo [24] to study the pathophysiology of vasogenic edema which is a known complication of many types of brain injury such as trauma, tumors, hemorrhages, infarcts, and infections [25]. Less well-recognized is the finding that florid angiogenesis occurs in the lesion site, making this model suitable for in vivo studies of cerebral angiogenesis as documented previously [26,27,28,29,30]. The use of this model allowed us to compare the VEGF-D expression with that of VEGF-A and -B [9], which was also documented using this model.…”

Section: Introductionmentioning

confidence: 99%

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Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury

Nag

Manias

Eubanks

et al. 2019

IJMS

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Alterations in the expression of the vascular endothelial growth factors (VEGF) A and B occur during blood–brain barrier (BBB) breakdown and angiogenesis following brain injury. In this study, the temporal and spatial expression of VEGF-D and VEGF receptors-2 and -3 (VEGFR-2 and VEGFR-3, respectively) was determined at the mRNA and protein level in the rat cortical cold-injury model over a period of 0.5 to 6 days post-injury. In order to relate endothelial VEGF-D protein expression with BBB breakdown, dual labeling immunofluorescence was performed using antibodies to VEGF-D and to fibronectin, a marker of BBB breakdown. In control rats, VEGF-D signal was only observed in scattered perivascular macrophages in the cerebral cortex. The upregulation of VEGF-D mRNA expression was observed in the injury site between days 0.5 to 4, coinciding with the period of BBB breakdown and angiogenesis. At the protein level, intracerebral vessels with BBB breakdown to fibronectin in the lesion on days 0.5 to 4 failed to show endothelial VEGF-D. Between days 0.5 to 6, an increased VEGF-D immunoreactivity was noted in the endothelium of pial vessels overlying the lesion site, in neutrophils, macrophages, and free endothelial cells within the lesion. The upregulation of VEGFR-2 and -3 mRNA and protein expression was observed early post-injury on day 0.5. Although there was concurrent expression of VEGF-A, VEGF-B, and VEGF-D post-injury, differences in their spatial expression during BBB breakdown and angiogenesis suggest that they have specific and separate roles in these processes.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury

Nag

Manias

Eubanks

et al. 2019

IJMS

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“…Similar patterns of endothelial cell activation are noted in cerebral edema, which is also associated with increased permeability of the BBB 45 . There are two main permeability barriers: the basement membrane and the endothelial cell.…”

Section: Discussionsupporting

confidence: 57%

Recent Research Trend for Ménièreʼs Disease

Nam¹

2017

Res Vestib Sci

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The ultrastructural organization of the blood labyrinthine barrier (BLB) was investigated in the human vestibular endorgan, the utricular macula, using postmortem specimens from individuals with documented normal auditory and vestibular function and surgical specimens from patients with intractable Meniere's disease. Transmission electron microscopic analysis of capillaries located in the normal human utricular stroma showed vascular endothelial cells with few pinocytotic vesicles, covered by a smooth and uniform basement membrane surrounded by pericyte processes. Meniere's disease specimens revealed differential ultrastructural pathological changes in the cellular elements of the microvasculature. With moderate degeneration of the BLB, there were numerous vesicles within the vascular endothelial cells (VECs), with increased numbers at the abluminal face, pericyte process detachment and disruption of the perivascular basement membrane surrounding the VECs. With severe degeneration of the BLB, there was severe vacuolization or frank apparent necrosis of VECs and loss of subcellular organelles. A higher severity of BLB degenerative changes was associated with a higher degree of basement membrane thickening and edematous changes within the vestibular stroma. This study presents the first ultrastructural analysis of the capillaries constituting the BLB in the human vestibular macula utricle from normal and Meniere's disease.In the inner ear, the term blood labyrinthine barrier (BLB) refers to the barrier between the vasculature and the inner ear fluids, either endolymph or perilymph 1, 2 . The BLB is critical for the maintenance of the inner ear fluid ionic homeostasis and for the prevention of the entry of deleterious substances into the inner ear 3 . By studying the penetration of dyes and drugs from the systemic circulation into the fluids of the inner ear, it can be shown that the BLB is selective and that the composition of the inner ear fluids is regulated and markedly different from that of blood or of other fluids such as cerebrospinal fluid 2 . Understanding the dynamics of the BLB is important to develop therapeutic drug delivery systems to the inner ear to block or enhance the BLB inflammatory response. The BLB in the cochlea is well studied in animal models 2,4,5 . Initial transmission electron microscopy (TEM) studies demonstrated that the BLB in the guinea pig stria vascularis and spiral ligament is composed of vascular endothelial cells (VECs) surrounded by a basement membrane 6 . More recent studies have noted that, in addition, the intrastrial BLB is composed of pericytes and perivascular-resident macrophage-like melanocytes [7][8][9][10][11] . The VECs line the interior surface of the blood vessels, connected by tight junctions, forming an interface between circulating blood and the rest of the vessel wall. Pericytes are the only cell type to intimately connect with VECs as they lie embedded within the endothelial basement membrane. The perivascular-resident macrophage-like melanocytes have foot pr...

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“…Interestingly, Nag et al [99] found only minimal expression of caspase-3 after ANG-1 production by the endothelium following cortical cold injury in rats. Further, Zhao et al [100] suggested that ANG-1 inhibited glycation end product-induced endothelial cell apoptosis.…”

Section: Regulation Of Bbb Function By Astrocyte-derived Factorsmentioning

confidence: 99%

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

Michinaga

Kōyama

2019

IJMS

202

143

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The blood-brain barrier (BBB) is a major functional barrier in the central nervous system (CNS), and inhibits the extravasation of intravascular contents and transports various essential nutrients between the blood and the brain. After brain damage by traumatic brain injury, cerebral ischemia and several other CNS disorders, the functions of the BBB are disrupted, resulting in severe secondary damage including brain edema and inflammatory injury. Therefore, BBB protection and recovery are considered novel therapeutic strategies for reducing brain damage. Emerging evidence suggests key roles of astrocyte-derived factors in BBB disruption and recovery after brain damage. The astrocyte-derived vascular permeability factors include vascular endothelial growth factors, matrix metalloproteinases, nitric oxide, glutamate and endothelin-1, which enhance BBB permeability leading to BBB disruption. By contrast, the astrocyte-derived protective factors include angiopoietin-1, sonic hedgehog, glial-derived neurotrophic factor, retinoic acid and insulin-like growth factor-1 and apolipoprotein E which attenuate BBB permeability resulting in recovery of BBB function. In this review, the roles of these astrocyte-derived factors in BBB function are summarized, and their significance as therapeutic targets for BBB protection and recovery after brain damage are discussed.

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Molecular Changes Associated with the Protective Effects of Angiopoietin-1 During Blood-Brain Barrier Breakdown Post-Injury

Cited by 16 publications

References 58 publications

Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury

Increased Expression of Vascular Endothelial Growth Factor-D Following Brain Injury

Recent Research Trend for Ménièreʼs Disease

Dual Roles of Astrocyte-Derived Factors in Regulation of Blood-Brain Barrier Function after Brain Damage

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