Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection

Diaz-Perez, A.; Lope-Piedrafita, S.; Perez, B.; Vazquez-Sufuentes, P.; Rodriguez-Garcia, M.; Briones, A. M.; Navarro, X.; Penas, C.; Jimenez-Altayo, F.

doi:10.1101/2024.10.15.618453

bioRxiv · 10.1101/2024.10.15.618453

Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection

Diaz-Perez, A.·Lope-Piedrafita, S.·Perez, B.·Vazquez-Sufuentes, P.·Rodriguez-Garcia, M.·Briones, A. M.·Navarro, X.·Penas, C.·Jimenez-Altayo, F.

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Abstract

Stroke induces brain injury, especially severe in hypertensive patients, and elevates mortality rates through non-neurological complications. However, the potential effects of a transient ischaemic episode on the peripheral vasculature of hypertensive individuals remain unclear. Here, we investigated whether transient cerebral ischaemia (90 min)/reperfusion (1 or 8 days) induces alterations in mesenteric resistance artery (MRA) properties in adult male spontaneously hypertensive rats (SHR). In addition, we assessed whether the reported cerebroprotective effects of suberoylanilide hydroxamic acid (SAHA; 50 mg/kg; administered intraperitoneally at 1, 4, or 6 h after reperfusion onset) extend long-term and include beneficial effects on MRAs. Functional and structural properties of MRAs were examined at 1- and 8-days post-stroke. Nuclei distribution, collagen content, and oxidative stress were assessed. Ischaemic brain damage was evaluated longitudinally using magnetic resonance imaging. Following stroke, MRAs from SHR exhibited non-reversible impaired contractile responses to the thromboxane A2 receptor agonist U46619. Stroke increased the MRA cross-sectional area, wall thickness, and wall/lumen ratio due to augmented collagen deposition. These changes were partially sustained 8 days later. SAHA did not improve U46619-induced contractions but mitigated stroke-induced oxidative stress and collagen deposition, preventing MRA remodelling at 24 h of reperfusion. Furthermore, SAHA induced sustained cerebroprotective effects over 8 days, including reduced brain infarct and oedema, and improved neurological scores. However, SAHA had minimal impact on chronic MRA contractile impairments and remodelling. These findings suggest that stroke causes MRA changes in hypertensive subjects. While SAHA treatment offers long-term protection against brain damage, it cannot fully restore MRA alterations.

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Diaz-Perez, A., Lope-Piedrafita, S., Perez, B., Vazquez-Sufuentes, P., Rodriguez-Garcia, M., Briones, A. M., Navarro, X., Penas, C., Jimenez-Altayo, F.. 2024-10-18. Temporary cerebral ischaemia impairs thromboxane A2 constriction and induces hypertrophic remodelling in peripheral mesenteric arteries of hypertensive rats: limited reversal despite long-term suberoylanilide hydroxamic acid cerebroprotection. https://doi.org/10.1101/2024.10.15.618453

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