Alcohol-Induced Alterations in the Vascular Basement Membrane in the Substantia Nigra of the Adult Human Brain
<p>Semi-quantitative grading scale used for analysis of the thickness and integrity of the vascular BM. Red dots symbolize erythrocytes. Each vessel was analyzed for both these parameters individually in five random visual fields per region, per sample for both gray and white matter. Grade I represents normal vessels. Grade II represents moderately damaged vessels. Grade III represents severely damaged vessels.</p> "> Figure 2
<p>Inter-group analysis of CD31+ vessels per visual field in the (<b>a</b>) <span class="html-italic">Pars Compacta</span> (SNpc) and (<b>b</b>) <span class="html-italic">Pars Reticulata</span> (SNpr) for the three studied groups in both gray and white matter. The bar plots indicate the average number of CD31+ vessels ± S.E. (Standard Error) seen per visual field; ** indicates a significant difference between the groups (<span class="html-italic">p</span> < 0.05 with Bonferroni correction is considered as significant). Distribution of CD31+ vessels per visual field in (<b>c</b>,<b>f</b>,<b>i</b>,<b>l</b>) group A (controls), (<b>d</b>,<b>g</b>,<b>j</b>,<b>m</b>) group B (age-matched alcoholics), and (<b>e</b>,<b>h</b>,<b>k</b>,<b>n</b>) group C (non-age-matched alcoholics). Red arrows indicate CD31+ vessels. Original magnification, 200×. Scale bars, 100 µm.</p> "> Figure 3
<p>Inter-group analysis of the increase in (<b>a</b>,<b>b</b>) thickness and (<b>c</b>,<b>d</b>) loss of integrity of the BM based on the expression of collagen-IV in the microvessels in the (<b>a,c</b>) gray matter and (<b>b</b>,<b>d</b>) white matter of the SN region. Group A represent controls, group B represents young alcoholics, whilst group C represents chronic alcoholics. The bar plots indicate the weighted average grading of all the visualized blood vessels in each group; ** indicates a significant difference between the groups (<span class="html-italic">p</span> < 0.05 with Bonferroni correction is considered as significant). Representative photomicrographs showing the different grades of BM thickness and integrity based on the expression of collagen-IV as visualized in the brain tissue material using immunohistochemistry (IHC) and immunofluorescence (IF) as follows: (<b>e</b>,<b>h</b>,<b>k</b>) grade I vessel with normal (baseline) thickness and unchanged integrity; (<b>f</b>,<b>i</b>,<b>l</b>) grade II vessel with moderate thickness and damaged integrity; (<b>g</b>,<b>j</b>,<b>m</b>) grade III vessel with extremely thickened and split BM. The pink and red arrows show the extent of thickening and loss of integrity as visualized using IHC and IF, respectively. In IF, green color shows the collagen-IV protein, whilst blue color shows DAPI-stained nuclei. Original magnification (IHC), 400×. Scale bars, 50 μm. Original magnification (IF), 1000×. Scale bars, 20 μm.</p> "> Figure 4
<p>Inter-group analysis of the increase in (<b>a</b>,<b>b</b>) thickness and (<b>c</b>,<b>d</b>) loss of integrity of the BM based on expression of laminin-111 in the microvessels in the (<b>a</b>,<b>c</b>) gray matter and (<b>b</b>,<b>d</b>) white matter of the SN region. Group A represent controls, group B represents young alcoholics, whilst group C represents chronic alcoholics. The bar plots indicate the weighted average grading of all the visualized blood vessels in each group; ** indicates a significant difference between the groups (<span class="html-italic">p</span> < 0.05 with Bonferroni correction is considered as significant). Representative photomicrographs showing the different grades of thickness and integrity of BM based on expression of laminin-111 as visualized in the brain tissue material using immunohistochemistry (IHC) and immunofluorescence (IF) as follows: (<b>e</b>,<b>h</b>,<b>k</b>) grade I vessel with normal thickness and unchanged integrity; (<b>f</b>,<b>i</b>,<b>l</b>) grade II vessel with moderate thickness and damaged integrity; (<b>g</b>,<b>j</b>,<b>m</b>) grade III vessel with extremely thickened and split BM. The pink and red arrows show the extent of thickening and loss of integrity as visualized using IHC and IF, respectively. In IF, green color shows the laminin-111 protein, whilst blue color shows DAPI-stained nuclei. Original magnification (IHC), 400×. Scale bars, 50 μm. Original magnification (IF), 1000×. Scale bars, 20 μm.</p> "> Figure 5
<p>Inter-group analysis of the increase in (<b>a</b>,<b>b</b>) thickness and (<b>c</b>,<b>d</b>) loss of integrity of the BM based on the expression of fibronectin in the microvessels in the (<b>a</b>,<b>c</b>) gray matter and (<b>b</b>,<b>d</b>) white matter of the SN region. Group A represent controls, group B represents young alcoholics, whilst group C represents chronic alcoholics. The bar plots indicate the weighted average grading of all the visualized blood vessels in each group; ** indicates a significant difference between the groups (<span class="html-italic">p</span> < 0.05 with Bonferroni correction is considered as significant). Representative photomicrographs showing the different grades of BM thickness and integrity based on expression of fibronectin as visualized in the brain tissue material using immunohistochemistry (IHC) and immunofluorescence (IF) as follows: (<b>e</b>,<b>h</b>,<b>k</b>) grade I vessel with normal (baseline) thickness and unchanged integrity; (<b>f</b>,<b>i</b>,<b>l</b>) grade II vessel with a moderate thickness and damaged integrity; (<b>g</b>,<b>j</b>,<b>m</b>) grade III vessel with extremely thickened and split BM. The pink and red arrows show the extent of thickening and loss of integrity as visualized using IHC and IF, respectively. In IF, green color shows the fibronectin protein whilst blue color shows DAPI-stained nuclei. Original magnification (IHC), 400×. Scale bars, 50 μm. Original magnification (IF), 1000×. Scale bars, 20 μm.</p> "> Figure 6
<p>Representative transmission electron microscopy (TEM) micrographs of ultrastructural changes observed in different grades of blood vessels in the gray matter of predominantly (<b>a</b>) controls and (<b>b</b>,<b>c</b>) alcoholics. The yellow lines indicate the outer borderline of the basement membrane (Bm). (<b>a</b>) Accumulation of lipolysosomes in the cytoplasm of the endothelial cell. Homogenous and smooth BM can be seen. (<b>b</b>) Endothelial cells with tight junctions and nearby neuron containing neuromelanin is seen. The vessel has a lamellar BM. (<b>c</b>) Endothelial cells with tight junctions and pericyte with nucleus can be seen. The vessel shows splitting of the BM. Abbreviations: Neu, neuron; Er, erythrocyte; Pn, nucleus of pericyte; En, endothelial cell; Tj, tight junction; Mth, mitochondria; Nm, neuromelanin; Ly, lipolysosomes. Original magnification, 12,000×. Scale bars, 500 nm.</p> "> Figure 7
<p>Representative scanning electron microscopy (SEM) micrographs of the vascular endothelium in the gray matter of predominantly (<b>a</b>) controls and (<b>b</b>) alcoholics. (<b>a</b>) Characteristic continuous endothelium (En) seen in the walls of SN microvessels in the lateral view. Original magnification, 7000×. (<b>b</b>) Ultrastructural changes observed in between neighboring endothelial cells on the luminal surface. Large paracellular pores (shown by a red line) and fenestrae (shown by a yellow line) can be seen on the luminal surfaces of endothelial cells. Original magnification, 6500×. Scale bars, 2 μm.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Human Autopsy Brain Tissue Collection
2.2. Immunohistochemistry Reactions
2.3. Immunofluorescence Reactions
2.4. Transmission (TEM) and Scanning (SEM) Electron Microscopy
2.5. Scoring System and Statistical Analysis
3. Results
3.1. Alcoholics Showed Significantly Less CD31+ Vessels Than Controls in Both Gray and White Matter
3.2. Alcoholics Showed Significant Increases in Collagen-IV Expression Coupled with Significant Losses of Vessel Integrity in Both Gray and White Matter
3.3. Expression of Laminin-111 Showed Significant Increases in Alcoholics Coupled with Significant Changes in the Vessel Integrity in Both Gray and White Matter
3.4. Expression of Fibronectin Was Significantly Upregulated in Alcoholics, Which Was Coupled with Significant Loss of Structural Integrity in Both Gray and White Matter
3.5. Increases in the Thickness or Expression of BM Glycoproteins Were Negatively Correlated with the Integrity of the BM
3.6. Ultrastructural Analysis of the Vascular Basement Membrane and BBB
4. Discussion
4.1. White Matter Has Significantly Fewer CD31+ Microvessels Than Gray Matter in Physiological Conditions
4.2. Alcohol Use Aggravates Decreased Microvascular Density in Both Gray and White Matter
4.3. Gray Matter Has Thinner and More Damaged Collagen-Iv-Containing Basement Membrane Than White Matter
4.4. The Dual Role of Upregulated Expression in Laminin-111
4.5. Increased Expression of Fibronectin Might Promote Endothelial Damage
4.6. Potential Diagnostic Applications
4.7. Limitations of the Present Study
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Primary Antibody * | Antibody Properties ** | Clone | Working Dilutions | Manufacturer | Catalogue No. |
---|---|---|---|---|---|
CD31 | Mouse monoclonal AB against human AG | JC70A | 1/30 | DakoCytomation (Glostrup, Denmark) | M0823 |
Collagen-IV | Mouse monoclonal AB against human AG | PHM-12 | 1/100 | Novocastra (Deer Park, IL, USA) | NCL-COLL-IV |
Laminin-111 | Rabbit polyclonal AB against human AG | - | 1/1000 | Arigo Biolaboratories (Hsinchu City, Taiwan) | ARG10736 |
Fibronectin | Rabbit Polyclonal AB against human AG | - | 1/400 | DakoCytomation (Glostrup, Denmark) | A0245 |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 07.00 ± 0.17 | 05.80 ± 0.14 | 05.03 ± 0.09 | <0.001 ** |
White Matter | 05.09 ± 0.14 | 03.83 ± 0.11 | 03.34 ± 0.07 | <0.001 ** |
pValue ‡ | <0.001 ** | <0.001 ** | <0.001 ** | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 05.55 ± 0.18 | 04.26 ± 0.16 | 03.52 ± 0.10 | <0.001 ** |
White Matter | 04.34 ± 0.12 | 02.56 ± 0.17 | 02.02 ± 0.08 | <0.001 ** |
pValue ‡ | <0.001 ** | <0.001 ** | <0.001 ** | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.084 | 1.102 | 1.195 | <0.001 ** |
White Matter | 1.121 | 1.143 | 1.187 | 0.009 ** |
pValue ‡ | 0.072 | 0.031 ** | 0.355 | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.063 | 1.130 | 1.158 | <0.001 ** |
White Matter | 1.115 | 1.160 | 1.201 | 0.002 ** |
pValue ‡ | 0.002 ** | 0.991 | 0.187 | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.201 | 1.245 | 1.343 | <0.001 ** |
White Matter | 1.116 | 1.195 | 1.216 | <0.001 ** |
pValue ‡ | <0.001 ** | 0.004 ** | <0.001 ** | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.173 | 1.209 | 1.241 | 0.012 ** |
White Matter | 1.121 | 1.216 | 1.296 | <0.001 ** |
pValue ‡ | <0.001 ** | 0.939 | 0.452 | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.132 | 1.192 | 1.249 | <0.001 ** |
White Matter | 1.179 | 1.213 | 1.280 | 0.005 ** |
pValue ‡ | 0.146 | 0.949 | 0.611 | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.163 | 1.226 | 1.295 | <0.001 ** |
White Matter | 1.188 | 1.257 | 1.344 | <0.001 ** |
pValue ‡ | 0.333 | 0.786 | 0.279 | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.214 | 1.219 | 1.396 | <0.001 ** |
White Matter | 1.169 | 1.213 | 1.360 | 0.003 ** |
pValue ‡ | 0.011 ** | 0.936 | 0.830 | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.176 | 1.251 | 1.326 | <0.001 ** |
White Matter | 1.174 | 1.227 | 1.318 | <0.001 ** |
pValue ‡ | 0.428 | 0.482 | 0.526 | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.145 | 1.158 | 1.217 | <0.001 ** |
White Matter | 1.185 | 1.317 | 1.380 | <0.001 ** |
pValue ‡ | 0.010 ** | <0.001 ** | 0.033 ** | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.122 | 1.159 | 1.210 | <0.001 ** |
White Matter | 1.162 | 1.240 | 1.339 | <0.001 ** |
pValue ‡ | 0.923 | 0.002 ** | 0.026 ** | - |
Controls (Group A) | Young Alcoholics (Group B) | Chronic Alcoholics (Group C) | p Value † | |
---|---|---|---|---|
Pars Compacta(SNpc) | ||||
Gray Matter | 1.132 | 1.135 | 1.248 | <0.001 ** |
White Matter | 1.082 | 1.215 | 1.298 | <0.001 ** |
pValue ‡ | <0.001 ** | 0.063 | <0.001 ** | - |
Pars Reticulata(SNpr) | ||||
Gray Matter | 1.158 | 1.181 | 1.261 | <0.001 ** |
White Matter | 1.097 | 1.173 | 1.247 | 0.273 |
pValue ‡ | <0.001 ** | 0.086 | <0.001 ** | - |
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Skuja, S.; Jain, N.; Smirnovs, M.; Murovska, M. Alcohol-Induced Alterations in the Vascular Basement Membrane in the Substantia Nigra of the Adult Human Brain. Biomedicines 2022, 10, 830. https://doi.org/10.3390/biomedicines10040830
Skuja S, Jain N, Smirnovs M, Murovska M. Alcohol-Induced Alterations in the Vascular Basement Membrane in the Substantia Nigra of the Adult Human Brain. Biomedicines. 2022; 10(4):830. https://doi.org/10.3390/biomedicines10040830
Chicago/Turabian StyleSkuja, Sandra, Nityanand Jain, Marks Smirnovs, and Modra Murovska. 2022. "Alcohol-Induced Alterations in the Vascular Basement Membrane in the Substantia Nigra of the Adult Human Brain" Biomedicines 10, no. 4: 830. https://doi.org/10.3390/biomedicines10040830
APA StyleSkuja, S., Jain, N., Smirnovs, M., & Murovska, M. (2022). Alcohol-Induced Alterations in the Vascular Basement Membrane in the Substantia Nigra of the Adult Human Brain. Biomedicines, 10(4), 830. https://doi.org/10.3390/biomedicines10040830