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Transcriptome Profiling Revealed Early Vascular Smooth Muscle Cell Gene Activation Following Focal Ischemic Stroke in Female Rats – Comparisons with Males
Lars Edvinsson
Chairman, Department Experimental Clinical Research
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1805-1346
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Genomics.
Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets.
Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCA as compared to the non-stroke control arteries from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common).
Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCA, and to a less pronounced degree in the non-occluded MCA. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of the differentially expressed genes) validated for this microarray did not reveal any sex differences. However, sex differences might be observed for other gene targets.
Keywords
Focal cerebral ischemia, transcriptomics, mRNA, gene regulation, female rats, sex differences, transcription factors, inflammation, endothelial function, pathway analysis
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CURRENT STATUS: Published
Editorial decision: Minor revision
On 19 Nov, 2020
Editor assigned
On 11 Nov, 2020
Submission checks complete
On 11 Nov, 2020
Editor invited
On 11 Nov, 2020
Version 1
Posted 17 Sep, 2020
Published
On 09 Dec, 2020
Published
On 09 Dec, 2020
No community comments so far
Review #2 received
Received 09 Oct, 2020
Editorial decision: Minor revision
On 09 Oct, 2020
Review #1 received
Received 02 Oct, 2020
Reviewer #2 agreed
On 01 Oct, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Reviewers invited
Invitations sent on 16 Sep, 2020
Editor assigned
On 07 Sep, 2020
Submission checks complete
On 06 Sep, 2020
Editor invited
On 06 Sep, 2020
First submitted
On 04 Sep, 2020
Metrics
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HTML Views: ...
Subject Areas
Epigenetics & Genomics
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This preprint is under consideration at BMC Genomics. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Transcriptome Profiling Revealed Early Vascular Smooth Muscle Cell Gene Activation Following Focal Ischemic Stroke in Female Rats – Comparisons with Males
Lars Edvinsson
Chairman, Department Experimental Clinical Research
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1805-1346
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
Editorial decision: Minor revision
On 19 Nov, 2020
Editor assigned
On 11 Nov, 2020
Submission checks complete
On 11 Nov, 2020
Editor invited
On 11 Nov, 2020
Version 1
Posted 17 Sep, 2020
Published
On 09 Dec, 2020
Published
On 09 Dec, 2020
No community comments so far
Review #2 received
Received 09 Oct, 2020
Editorial decision: Minor revision
On 09 Oct, 2020
Review #1 received
Received 02 Oct, 2020
Reviewer #2 agreed
On 01 Oct, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Reviewers invited
Invitations sent on 16 Sep, 2020
Editor assigned
On 07 Sep, 2020
Submission checks complete
On 06 Sep, 2020
Editor invited
On 06 Sep, 2020
First submitted
On 04 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Epigenetics & Genomics
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published version at BMC Genomics.
Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets.
Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCA as compared to the non-stroke control arteries from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common).
Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCA, and to a less pronounced degree in the non-occluded MCA. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of the differentially expressed genes) validated for this microarray did not reveal any sex differences. However, sex differences might be observed for other gene targets.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8