Numerous recent studies have identified correlations between greater large artery stiffness and cognitive impairment and/or Alzheimer’s disease (AD). However, the mechanisms behind these relations are currently unknown. AD‐related pathology is characterized by an accumulation of amyloid‐β and tau protein aggregates. Greater large artery stiffness, amyloid‐β, and tau pathology are all independently associated with impaired cerebrovascular function. These cerebrovascular impairments may lead to a reduced cerebral perfusion, a potential cause of cognitive impairment. Thus, we hypothesized that greater large artery stiffness and AD‐related pathology would interact to impair cerebral perfusion. In order to examine the effects of elevated large artery stiffness, we studied the elastin haploinsufficient (Eln+/−) mouse. We previously established that Eln+/− mice have greater aortic stiffness when compared with Eln+/+ mice, similar to the increases in large artery stiffness that occur with aging. To understand the potential interaction of large artery stiffness and AD‐related pathology, we crossed Eln+/− mice with the 3xTg‐AD mouse model (mutant transgenes for amyloid precursor protein, presenilin‐1, and tau). The groups consisted of male and female mice at 14–16 months of age with the following genotypes: Eln+/+ (n=13), Eln+/− (n=13), Eln+/+ x 3xTg‐AD (n=5), and Eln+/− x 3xTg‐AD (n=8). Cerebral perfusion was obtained in anesthetized mice by arterial spin labeling MRI under both normoxic and hypercapnic (5% CO2) conditions. Perfusion through the hippocampus was analyzed using JIM image analysis software (Xinapse Systems). Among non‐3xTg‐AD mice, Eln+/− mice had a 20% lower hippocampal perfusion compared with Eln+/+ mice during normoxia (p=0.04). In response to hypercapnia, hippocampal perfusion increased by 34±8% in Eln+/− mice, which was greater than the increased perfusion of 16±5% in Eln+/+ mice (p=0.03). Among 3xTg‐AD mice, there was no difference in hippocampal perfusion during normoxia for Eln+/− x 3xTg‐AD vs. Eln+/+ x 3xTg‐AD mice (p=0.34). In contrast, in response to hypercapnia Eln+/− x 3xTg‐AD mice had only a 5±8% increase in hippocampal perfusion compared with a 21±4% increase in perfusion in Eln+/+ x 3xTg‐AD mice (p=0.05). There was an interaction between Eln and 3xTg‐AD genotype for the increase in hippocampal perfusion with hypercapnia (p=0.03), but no interaction for hippocampal perfusion during normoxia (p=0.18). In conclusion, these results suggest large artery stiffness leads to a decline in hippocampal perfusion under normoxia, but augments the hippocampal perfusion response to hypercapnia. The presence of AD‐related pathology may negate the effects of large artery stiffness on hippocampal perfusion under normoxic conditions. The combination of greater large artery stiffness and AD‐related pathology lead to a reduced hippocampal perfusion response to hypercapnia. Support or Funding Information Funded by the Oregon Alzheimer’s Tax Checkoff Fund
Introduction: With advancing age, there are changes in the structural and material properties of the arterial wall. While the age-related increase in stiffness is well described for large arteries, less is known about the structural changes to cerebral arteries with age. In response to increased blood pressure, as occurs with aging, arteries typically undergo remodeling that includes smooth muscle cell proliferation and collagen accumulation. This remodeling contributes to increased stiffness and reduces pulse pressure dampening, potentially leading to damage to arterioles and capillaries. We hypothesized that old cerebral arteries would display greater stiffness, wall thickness, collagen content, and smooth muscle content compared with young cerebral arteries. Methods: We studied old male (n=10, 24-27 months) and young male (n=9, 4-7 months) C57BL/6 mice. For measures of stiffness, isolated posterior cerebral arteries were exposed to pulsatile pressure (37.5 to 87.5 mmHg, 400 pulses/min) for 30 minutes. Artery diameters during the pulsation were recorded and used to calculate distension, β-stiffness index, and Peterson modulus of elasticity (EP). In sections of the middle cerebral arteries, total wall thickness and total collagen were measured in Masson’s trichrome-stained arteries. Collagen-1 and α-smooth muscle actin content were measured by immunofluorescence in middle cerebral artery sections. Data were analyzed by a Shapiro-Wilks test for normality, and young and old groups were compared by student’s t-test. Group comparisons for β-stiffness, EP, and percent change in diameter were made using a Mann-Whitney test. A p<0.05 was considered statistically significant. Data are mean±SD. Results: Cerebral arteries from young mice, compared with old mice, had a higher distensibility during the application of pulsatile pressure, measured by the percent change in diameter (8.0±4.0% vs. 5.1±2.5%, p=0.03) or absolute change in diameter (12.0±5.4 μm vs. 7.8±3.8 μm, p=0.03). Cerebral artery stiffness, calculated by β-stiffness index (13.1±6.5 AU vs. 21.9±13.8 AU, p=0.03) and EP (777±384 kPa 102 vs.1293±816 kPa 102, p=0.03) was lower in young mice compared with old mice. There was no difference in cerebral artery wall thickness between groups (6.9±3.0 μm vs. 9.6±2.3 μm, p=0.08). Cerebral arteries from old mice had greater amounts of α-smooth muscle actin compared to young mice (1.4±0.2 AU vs. 1.0±0.2 AU, p=0.009). Interestingly, cerebral arteries from old mice had lower collagen-1 compared to young mice (0.8±0.1 vs. 1.0±0.1 AU, p=0.01), but the opposite trend was observed for total collagen (26.3±13.6 AU vs. 17.6±9.6, p=0.06). Conclusion: These results demonstrate that advancing age results in increased functional stiffness of cerebral arteries. An age-related increase in smooth muscle is a potential cause of higher cerebral artery stiffness. This project was funded by NIH R01 AG064016 and the Oregon Medical Research Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Reductions in cerebral blood flow (CBF) and the CBF response to hypercapnia (cerebrovascular reactivity) are implicated in the progression of Alzheimer's disease and other related dementias. Recent data suggest that 20%–30% of individuals exhibit vertebral artery hypoplasia (VAH), and as a result, have a significant difference in left and right vertebral artery blood flow. Consequently, in those with VAH, the regions of the brain that the posterior circulation supplies may be at risk of hypoperfusion. Furthermore, people with VAH may rely more on the systemic circulation to regulate CBF, rather than on local regulation. The purpose of this study was to determine the effect of VAH on cerebral blood flow regulation in habitually active, sex and age matched adults. We hypothesized that during normoxia, and in response to hypercapnia, adults with VAH (n=10) would have lower global flow and lower global cerebrovascular reactivity, basilar artery (BA) reactivity, and internal carotid artery (ICA) reactivity compared with adults that did not exhibit VAH (Control, n=10). Participants underwent a 4D flow MRI scan in the supine position to determine regional and global blood flow during normoxia and hypercapnia (4% and 6% CO2). 4D flow MRI allows for flow analysis of multiple vessels with full volumetric coverage of any vascular region of interest. Reactivity was calculated as the linear relationship between blood flow and end‐tidal CO2. Global flow was calculated as the sum of the flow in the BA and ICAs. Global flow was significantly lower in VAH participants compared with control participants during normoxia (VAH: 478±26 ml/min; Control: 580±44 ml/min; p<0.05), 4% CO2 (VAH: 493±25 ml/min; Control: 631±47 ml/min; p<0.05), and 6% CO2 (VAH: 533±31 ml/min; Control: 682±48 ml/min; p<0.05). Compared to control participants, VAH participants had significantly lower global cerebrovascular reactivity (VAH: 6.2±2.0 ml/min/mmHg; Control: 11.0±1.6 ml/min/mmHg; p<0.05), BA reactivity (VAH: 1.2±0.5 ml/min/mmHg; Control: 2.6±0.4 ml/min/mmHg; p<0.05), and ipsilateral (same side as hypoplastic vertebral artery) ICA reactivity (VAH: 2.4±0.8 ml/min/mmHg; Control: 4.3±0.7 ml/min/mmHg; p<0.05) to hypercapnia. Additionally, there was a trend for lower contralateral ICA reactivity (VAH: 2.6±0.8 ml/min/mmHg; Control: 4.2±0.6 ml/min/mmHg; p=0.06) in VAH participants compared with control participants. These results suggest that individuals with VAH are not only affected in the immediate posterior cerebral circulation, but CBF is also affected globally, despite the bilateral symmetry of the brain and the collateral flow provided by the Circle of Willis. Future studies should consider the prevalence of hypoplasia in the cerebrovasculature in order to determine its relevance to cerebrovascular pathologies.Support or Funding InformationNIH HL 118154, Wisconsin Alumni Research Foundation, Hilldale Undergraduate/Faculty Research FellowshipThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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