Hypertension Fails to Disrupt White Matter Integrity in Young Or Aged Fisher (F44) Cyp1a1Ren2 Transgenic Rats

Holland, Philip R.; Pannozzo, Mercede Alcina; Bastin, Mark E.; McNeilly, Alison D.; Ferguson, Karen; Caughey, Sarah; Jansen, Maurits A.; Merrifield, Gavin D.; Marshall, Ian; Mullins, John J.; Sutherland, Calum; Horsburgh, Karen

doi:10.1038/jcbfm.2014.201

Cited by 10 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that the volume index of GM/TIV gradually decreased, whereas the WM/TIV increased from 10 to 80 weeks in both groups. One preclinical study on hypertension and white matter disruption in inducible hypertensive rats reported that hypertension fails to disrupt white matter integrity in young or aged rats, which is consistent with our findings ( Holland et al, 2015 ). Regional brain changes in aging adults with hypertension have confirmed white matter injury ( Sabisz et al, 2019 ).…”

Section: Discussionsupporting

confidence: 92%

Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study

Yang

Zhang

Ren³

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

The influence of hypertension and aging alone on brain structure has been described extensively. Our understanding of the interaction of hypertension with aging to brain morphology is still limited. We aimed to detect the synergistic effects of hypertension and aging on brain morphology and to describe the evolution patterns of cerebral atrophy from spatial and temporal perspectives. In 8 spontaneously hypertensive rats (SHRs) and 5 Wistar-Kyoto rats, high-resolution magnetic resonance imaging scans were longitudinally acquired at 10, 24, 52, and 80 weeks. We analyzed the tissue volumes of gray matter, white matter, cerebral spinal fluid, and total intracranial volume (TIV), and then evaluated gray matter volume in detail using voxel-based morphometry (VBM) and region of interest-based methods. There were interactive effects on hypertension and aging in tissue volumes of gray matter, white matter, and TIV, of which gray matter atrophy was most pronounced, especially in elderly SHRs. We identified the vulnerable gray matter volume with combined effects of hypertension and aging in the septal region, bilateral caudate putamen, hippocampus, primary somatosensory cortex, cerebellum, periaqueductal gray, right accumbens nucleus, and thalamus. We automatically extracted the septal region, anterior cingulate cortex, primary somatosensory cortex, caudate putamen, hippocampus, and accumbens nucleus and revealed an inverted-U trajectory of volume change in SHRs, with volume increase at the early phase and decline at the late phase. Hypertension interacts with aging to affect brain volume changes such as severe atrophy in elderly SHRs.

show abstract

Section: Discussionsupporting

confidence: 92%

Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study

Yang

Zhang

Ren³

et al. 2021

Front. Aging Neurosci.

View full text Add to dashboard Cite

show abstract

“…Recent evidence from animal models also suggest that hypertension is not the key driver of white matter changes. 36,37 Our results show that some radiologic, pathologic, and cognitive features of human SVD can be recapitulated in a mouse model by common carotid stenosis. Our findings also provide evidence that hypoperfusion may precipitate SVD-like disease culminating in a progressive brain and gliovascular pathology.…”

Section: Discussionmentioning

confidence: 63%

Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

Holland

Searcy

Salvadores

et al. 2015

J Cereb Blood Flow Metab

Self Cite

125

View full text Add to dashboard Cite

Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood-brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies. Keywords: cognition; diffusion-tensor imaging; hypoperfusion; magnetic resonance imaging; small vessel disease INTRODUCTION Cerebral small vessel disease (SVD) is a major cause of age-related cognitive decline and dementia. Journal of Cerebral Blood1 Hypertension is proposed to be a common risk factor (although it explains only a small proportion of imaging-determined SVD) and cerebral amyloid angiopathy is commonly present on pathologic examination.2,3 Clinically, SVD is associated with early impairment of attention and executive function with slowing of information processing and motor deficits.1 These clinical manifestations result primarily from the occurrence of lesions in the cerebral white matter, multiple lacunes within subcortical structures, atrophy, and, in some cases, microbleeds in deep gray matter, white matter, or at the corticosubcortical junction, identified by neuroimaging.2,4 White matter lesions, associated with increased extracellular fluid, varying degrees of myelin and axonal pathology, and glial responses, are predominantly detected as hyperintense regions on fluid attenuation inversion recovery and T2-weighted magnetic resonance imaging (MRI).5 Lacunes, which present as hypointense regions on fluid attenuation inversion recovery or T1-weighted MRI or hyperintense on T2-weighted MRI, are small deep cavities

show abstract

“…Long‐term induction of hypertension in aged Cyp1a1‐Ren2 rats with a high‐fat diet have been shown to have microstructural alterations but no white matter lesions (Holland et al. ). These modest changes, as well as the modest changes seen in our work, are an indication that this model could be beneficial in observing the mechanisms at play in the human condition.…”

Section: Discussionmentioning

confidence: 99%

Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning

et al. 2019

View full text Add to dashboard Cite

Hypertension is a major health concern in the developed world, and its prevalence increases with advancing age. The impact of hypertension on the function of the renal and cardiovascular systems is well studied; however, its influence on the brain regions important for cognition has garnered less attention. We utilized the Cyp1a1‐Ren2 xenobiotic‐inducible transgenic rat model to mimic both the age of onset and rate of induction of hypertension observed in humans. Male, 15‐month‐old transgenic rats were fed 0.15% indole‐3‐carbinol (I3C) chow to slowly induce renin‐dependent hypertension over a 6‐week period. Systolic blood pressure significantly increased, eventually reaching 200 mmHg by the end of the study period. In contrast, transgenic rats fed a control diet without I3C did not show significant changes in blood pressure (145 mmHg at the end of study). Hypertension was associated with cardiac, aortic, and renal hypertrophy as well as increased collagen deposition in the left ventricle and kidney of the I3C‐treated rats. Additionally, rats with hypertension showed reduced savings from prior spatial memory training when tested on the hippocampus‐dependent Morris swim task. Motor and sensory functions were found to be unaffected by induction of hypertension. Taken together, these data indicate a profound effect of hypertension not only on the cardiovascular‐renal axis but also on brain systems critically important for learning and memory. Future use of this model and approach may empower a more accurate investigation of the influence of aging on the systems responsible for cardiovascular, renal, and neurological health.

show abstract

Hypertension Fails to Disrupt White Matter Integrity in Young Or Aged Fisher (F44) Cyp1a1Ren2 Transgenic Rats

Cited by 10 publications

References 15 publications

Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study

Evolution of Brain Morphology in Spontaneously Hypertensive and Wistar-Kyoto Rats From Early Adulthood to Aging: A Longitudinal Magnetic Resonance Imaging Study

Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease

Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning

Contact Info

Product

Resources

About