Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation
<p>Changes in diameter of isolated middle cerebral arteries (MCAs) in response to step increases in intraluminal, flow (Δ0, Δ10, Δ20, Δ30, Δ40 mmHg between inflow and outflow cannulas) from intact rats and from rats after traumatic brain injury (TBI) in the absence and presence of SQ 29,548 (10<sup>−6</sup> mol/L) an inhibitor of thromboxane A<sub>2</sub> receptor (TP). Asterisks indicate significant differences * <span class="html-italic">p</span> < 0.05 vs. Intact flow and Intact flow with SQ 29,548 (<span class="html-italic">n</span> = 16, <span class="html-italic">n</span> = 8 in each group).</p> "> Figure 2
<p>Shows the pressure (P)- or flow (F)-induced decreases in diameter alone, or the additive effect of pressure + flow on the diameter of MCA from intact rats. Additionally, <a href="#ijms-22-06624-f002" class="html-fig">Figure 2</a> shows that traumatic brain injury (TBI) significantly reduced the pressure (P)-, flow (F)-, and thus combined pressure + flow (P+F)-induced constrictions of MCAs (* indicates significant changes from Intact, # from P alone and F alone, and & from P+F (<span class="html-italic">n</span> = 24, data are mean ± SEM, <span class="html-italic">p</span> < 0.05) Moreover, this figure shows that HET0016 (10<sup>−6</sup> mol/L), an inhibitor of cytochrome P450 4A (CYP450 4A), inhibited substantially and significantly the constriction induced by pressure + flow (<span class="html-italic">n</span> = 6 in each group).</p> "> Figure 3
<p>In middle cerebral arteries (MCAs) isolated from intact rats, lower concentration of arachidonic acid (AA), after initial dilations, (<b>left</b> panel), elicited constrictions (<b>right</b> panel), whereas higher concentration of AA elicited only constriction. After traumatic brain injury (TBI), AA-induced responses were significantly reduced. Data are mean ± SEM of normalized diameter %. (*, **, # indicate <span class="html-italic">p</span> < 0.05).</p> "> Figure 4
<p>This figure shows the mRNA expressions of the cytochrome isoforms Cyp4a1 and Cyp4a3 in middle cerebral arteries (MCAs) of INTACT and TBI rats, which were substantially reduced after TBI (<span class="html-italic">n</span> = 6 in each group).</p> "> Figure 5
<p>Changes in diameter of isolated middle cerebral arteries (MCAs) in response to 20-hydroxyeicosatetraenoic acid (20-HETE, 10<sup>−7</sup> mol/L) metabolite of cytochrome P450 4A enzyme (CYP450 4A) and U46619 (10<sup>−7</sup> mol/L and 10<sup>−6</sup> mol/L a stable agonist of TP receptors, intact and after traumatic brain injury (TBI). Data are mean ± SEM. Asterisks indicate significant differences (* <span class="html-italic">p</span> < 0.05 from zero, Intact 20-HETE 10<sup>−7</sup> ** <span class="html-italic">p</span> < 0.05 vs. TBI 20-HETE 10<sup>−7</sup> and Intact U46619 10<sup>−7</sup>, Intact U46619 10<sup>−6</sup> ** <span class="html-italic">p</span> < 0.05 TBI U46619 10<sup>−6</sup> Ʃn= 24, <span class="html-italic">n</span> = 6 in each group).</p> "> Figure 6
<p>This figure shows the role of impaired pressure- and flow-sensitive mechanisms in the development of traumatic brain injury (TBI)-induced vasomotor dysfunction and brain edema. In normal, intact conditions, pressure- and flow-sensitive mechanisms maintain—in a wide range—a relatively constant cerebral blood flow despite of increasing perfusion pressure (autoregulation). After TBI, the impairment of these mechanisms develops, thus we propose that blood flow would increase as a function of pressure. In addition, in the lack of appropriate constrictions of larger and smaller arteries—not only CBF, intracranial volume and thus pressure increases as perfusion pressure increases—but also the distal microvessels—part of the blood brain barrier—become exposed to higher intraluminal pressure. These, together with the mediators released from the injured brain tissue, could lead to the opening of BBB, leakage of fluid, and various molecules, contributing to the development of edema and brain tissue injury.</p> ">
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Traumatic Brain Injury (TBI)
2.3. Isolation of Rat Middle Cerebral Arteries and Use of Flow-Chamber to Obtain Vasomotor Responses
2.4. Myogenic Tone and Flow-Induced Responses of Isolated Cerebral Arteries
2.5. Administration of Vasoactive Agents
2.6. Quantitative Real-Time qRT-PCR
2.7. Statistical Analysis
3. Results
4. Discussion
4.1. Traumatic Brain Injury and Consequences
4.2. Traumatic Brain Injury Impairs Pressure and Flow Sensitive Vasomotor Mechanisms
4.3. Consequences of the TBI-Impaired Mechanosensitive Vasomotor Mechanisms on the Autoregulation of CBF
4.4. Limitation of the Present Study
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Szenasi, A.; Amrein, K.; Czeiter, E.; Szarka, N.; Toth, P.; Koller, A. Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation. Int. J. Mol. Sci. 2021, 22, 6624. https://doi.org/10.3390/ijms22126624
Szenasi A, Amrein K, Czeiter E, Szarka N, Toth P, Koller A. Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation. International Journal of Molecular Sciences. 2021; 22(12):6624. https://doi.org/10.3390/ijms22126624
Chicago/Turabian StyleSzenasi, Annamaria, Krisztina Amrein, Endre Czeiter, Nikolett Szarka, Peter Toth, and Akos Koller. 2021. "Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation" International Journal of Molecular Sciences 22, no. 12: 6624. https://doi.org/10.3390/ijms22126624
APA StyleSzenasi, A., Amrein, K., Czeiter, E., Szarka, N., Toth, P., & Koller, A. (2021). Molecular Pathomechanisms of Impaired Flow-Induced Constriction of Cerebral Arteries Following Traumatic Brain Injury: A Potential Impact on Cerebral Autoregulation. International Journal of Molecular Sciences, 22(12), 6624. https://doi.org/10.3390/ijms22126624