Differential Left and Right Carotid Artery Blood Flow and Altered Hippocampal Mitochondrial Function After Transverse Aortic Constriction in Aging Rats.

Pena, G. S.; Liu, Y.; Canellas Da Silva, M.; Ranadive, S. M.; Smith, J. C.; Kuzmiak-Glancy, S.

doi:10.1101/2025.01.15.633217

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bioRxiv · 10.1101/2025.01.15.633217

Differential Left and Right Carotid Artery Blood Flow and Altered Hippocampal Mitochondrial Function After Transverse Aortic Constriction in Aging Rats.

Pena, G. S.·Liu, Y.·Canellas Da Silva, M.·Ranadive, S. M.·Smith, J. C.·Kuzmiak-Glancy, S.

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Abstract

BackgroundThe hippocampus is a key brain structure that has been implicated in vascular dementia etiology and is highly sensitive to changes in cerebral blood flow. Brain hypoperfusion in cardiovascular disease may facilitate neurodegeneration in the hippocampus by limiting substrate transport and metabolism. While most animal studies have relied on artery occlusion to lower brain blood flow, brain hypoperfusion can also stem from mechanical damage resulting from high blood flow velocity and pulsatility. This study assessed, within the same rodent, whether high and low cerebral blood flow differentially affected hippocampal glucose transport protein expression, mitochondrial fuel oxidation, and expression of mitochondrial quality control proteins. Methods and Results4-week-old male and female Sprague-Dawley rats underwent transverse aortic constriction (TAC, n=13) or control (SHAM, n=18) surgeries. Bilateral carotid artery diameter and blood flow were measured 20-, 30-, and 40 weeks post-surgery. Right and left hippocampal mitochondrial respiration and expression of glucose transporters and mitochondrial quality control proteins were measured 40 weeks post-surgery. Right carotid blood flow velocity and pulsatility were highest in the right and lowest in the left carotid of TAC animals (p<0.05). Complex I (p=0.057), Complex I&II (p<0.05), and Complex II uncoupled (p<0.05) respiration rates were lower in the right hippocampus of TAC when compared to the left, and markers of mitochondrial fusion were upregulated in TAC compared to SHAM (p<0.05). ConclusionsWhile both limited and pulsatile blood flow alter mitochondrial fusion markers, only pulsatile flow impairs mitochondrial respiration, suggesting turbulent hemodynamics may drive metabolic dysfunction in vascular dementia. Clinical PerspectiveO_ST_ABSWhat is new?C_ST_ABSO_LIHigh blood velocity and pulsatility impairs hippocampal mitochondrial respiration while reduced blood flow does not. C_LIO_LIHippocampal protein expression of mitochondrial fusion and unfolded protein response markers is upregulated in response to altered carotid blood flow, but protein expression of endothelial and neuronal glucose transporters is unaffected. C_LIO_LIHippocampal mitochondrial respiration and protein expression of mitochondrial dynamics markers differs between male and females. C_LI What are the clinical implications?O_LIBrain hypoperfusion stemming from high blood velocity and pulsatility negatively impacts glucose oxidation by brain mitochondria to a greater degree than hypoperfusion stemming from decreased brain blood flow, and optimal treatment of vascular dementia may be best informed by vascular hemodynamic phenotype rather than cortical perfusion alone. C_LIO_LIAlterations in mitochondrial structure and function may precede changes in glucose transport during brain hypoperfusion, demonstrating the potential importance of treating mitochondrial impairments in vascular dementia. C_LIO_LINonstandard Abbreviations and Acronyms C_LI

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Pena, G. S., Liu, Y., Canellas Da Silva, M., Ranadive, S. M., Smith, J. C., Kuzmiak-Glancy, S.. 2025-01-19. Differential Left and Right Carotid Artery Blood Flow and Altered Hippocampal Mitochondrial Function After Transverse Aortic Constriction in Aging Rats.. https://doi.org/10.1101/2025.01.15.633217

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