(555.3) Impaired mechanotransduction of small cerebral arteries after traumatic brain injury. Role of arachidonic acid pathway dysfunction

Poster Board Number: E63

Akos Koller (University of Physical Education, Semmelweis University, New York Medical College), Annamaria Szenasi (Semmelweis University), Krisztina Amrein (University of Pecs), Endre Czeiter (University of Pecs), Nikolett Szarka (University of Pecs, MTA-PTE Clinical Neuroscience MR Research Group), Peter Toth (MTA-PTE Clinical Neuroscience MR Research Group, University of Pecs)

Background: Healthy functioning of the brain requires a precise autoregulation of cerebral blood flow, which in part is achieved by the pressure and flow sensitive vasomotor mechanisms. Traumatic brain injury (TBI) frequently occurs worldwide, resulting in brain diseases with high morbidity and mortality. Here, we hypothesized that TBI impairs the autoregulatory mechanisms, namely the pressure- and flow-induced constrictions of isolated rat middle cerebral arteries (MCAs).

Methods: TBI was induced in anaesthetized rats by weight drop model, and then MCAs were isolated and transferred into a pressure-flow chamber. Changes in internal diameter in response to hemodynamic forces and vasoactive drugs were measured by a video-microscopy.

Results: In MCAs from intact rats, increases in pressure-, flow- and pressure + flow elicited constrictions (max.: -26 ± 1.7; -26 ± 1.9; and -52 ± 2.8 µm, p lt; 0.05). Flow-induced constrictions were significantly reduced by HET0016, an inhibitor of cytochrome P450 4A (CYP450 4A) or in the presence of thromboxane-prostanoid (TP receptor) antagonist SQ 29,548. Both responses were significantly reduced after TBI. Arachidonic acid, (AA, 10−7 M), and CYP450 4A metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) elicited constrictions of intact MCA (-26 ± 2.3% and -31 ± 3.6%), which were significantly reduced after TBI (to -11 ± 1.3% and -16 ±2.5%). The TP receptor agonist U46619 (10−7 M) elicited substantial constrictions of MCA from intact rats (-21 ± 3.3%), which were also significantly reduced, after TBI (to -16 ± 2.4%).

Conclusions: Both pressure and flow-induced constrictions of MCA were impaired by traumatic brain injury, likely due to the reduced ability of cytochrome P450 4A to convert arachidonic acid to constrictor prostaglandins (cPGs) and the mitigated sensitivity of thromboxane-prostanoid receptors to cPGs. We propose that the impairment of autoregulatory vasomotor mechanisms contribute to the TBI-induced human brain diseases, such as headache, disruption of blood brain barrier, brain edema, Alzheimer-type diseases and vascular dementia.

Support or Funding Information

Funding: National Research, Development and Innovation Office Fund, OTKA K 132596, NKFI-FK123798 and TKP2020-NKA-17 Institutional Excellence Program at University of Physical Education, Semmelweis University.