Cerebral artery reactivity in young, adult, and aged APOE3 and APOE4 mice

Abstract

Introduction Alzheimer's disease (AD) is the most common form of dementia and is the 6th leading cause of death in the US. Growing evidence supports a link between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has neutral risk for developing AD, whereas APOE4 increases AD risk. In order to study APOE-mediated processes, cerebral vessels were isolated from mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2-Apoetm3(APOE*4)Mae N8)(Taconic Labs). Our objective was to determine whether allelic differences altered vascular function by assessing mechanical characteristics and vascular reactivity in the posterior cerebral artery (PCA) isolated from young (Y, 3mo), adult (A, 12mo) and aged (Aged, 18-22mo), homozygous APOE3 and APOE4, male and female mice. We hypothesize that APOE4 expression alters PCA structure/function compared to PCAs isolated from age matched APOE3 mice. Methods PCAs were rapidly isolated from age matched male and female, APOE3 and APOE4 mice, cleaned of connective tissue, cut into 5mm segments, and cannulated in an arteriograph chamber to assess mechanical characteristics and vascular reactivity (myogenic tone (MT) in the absence and presence of the non-specific NOS inhibitor, L-NAME). Active/passive wall tension, wall thickness, distensibility, stress/strain and MT was measured with stepwise increases in intraluminal pressure (10mm Hg to 140mm Hg). Results Our preliminary data suggests: PCAs from APOE3 and APOE4 mice exhibited similar MT. L-NAME inhibition of NOS unmasked MT in PCAs from APOE3 and APOE4 mice. L-NAME - induced MT was similar in Y, A and Aged APOE3 mice, where Y APOE4 mice exhibited greater L-NAME-induced tone than A and Aged (P<0.05). When challenged with 60mM [K+]o, all groups showed similar % constriction. Passive wall tension was similar in Y, A, and Aged APOE3 mice, where wall tension significantly decreased with aging in APOE4 mice (P<0.05). Wall thickness tended to increase with age in APOE3 mice, while wall thickness significantly decreased in aged APOE4 mice (P<0.05). Finally, Y APOE3 mice exhibited a rightward shift in stress vs strain, compared to A, and no difference was observed in vessels from A and Aged APOE3 mice. In contrast, PCAs from Y and A, APOE4 mice exhibited similar stress vs strain values. Interestingly, stress vs strain values in aged APOE4 PCAs were shifted to the left, and exhibited significantly different strain values for given values of stress at physiologically relevant pressures (P<0.05). Summary/Conclusions Our data suggests PCA vascular structure/function from APOE3 mice exhibit “normal” aging characteristics, whereas PCAs from APOE4 mice exhibit delayed changes in vascular structure/function. This data provides possible mechanisms for elevated cerebral blood flow in Y human and mice carrying the APOE4 allele vs aged matched APOE3.