Carotid Artery Reactivity in Young, Adult, and Aged APOE3 and APOE4 Mice

Abstract

IntroductionAlzheimer’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). Interestingly, variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has a neutral risk for developing AD, whereas APOE4 increases AD risk. In order to study APOE‐mediated processes in large arteries, carotid arteries (CAs) 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 expression alters CA vascular function by assessing mechanical characteristics and vascular reactivity in the left main CA 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 CA vascular reactivity, along with vascular structure compared to CAs isolated from age matched APOE3 mice.MethodsCAs were rapidly isolated from age matched male and female, APOE3 and APOE4 mice, cleaned of connective tissue, cut into 8mm segments, and cannulated in an arteriograph chamber to assess vascular reactivity via myogenic tone (MT) and phenylephrine (PE)‐induced constriction in the absence and presence of the non‐specific NOS inhibitor, L‐NAME. In addition, passive wall tension, arterial wall thickness, vascular distensibility, and arterial stress/strain were measured at intraluminal pressures ranging from 10mm Hg to 140mm Hg for assessment of age‐related changes in arterial structure/function.ResultsCAs from APOE3 and APOE4 mice did not exhibit MT in the absence or presence of L‐NAME. PE‐induced constriction in CA from APOE3 mice tended to decrease with age, while PE‐induced constriction in CA from A APOE4 mice were significantly greater than PE‐induced constriction in CAs from Y (P<0.05) or Aged (P<0.05) mice. In the presence of L‐NAME, PE‐induced constrictions were significantly increased in all mice at all ages (P<0.05). Wall thickness was similar in Y, A and Aged APOE3 and APOE 4 mice. Finally, CA from Y APOE3 mice exhibited a rightward shift in stress vs strain, compared to CAs from A and Aged mice. In contrast, CAs from Y and A, APOE4 mice exhibited similar stress vs strain values. Stress vs strain values in Aged APOE4 CAs were significantly shifted to the left of CA from A APOE4 mice suggesting greater arterial stiffening in Aged APOE4 mice at physiologically relevant intraluminal pressures (P<0.05).Summary/ConclusionsThese data suggest that CA vascular structure/function in APOE3 mice exhibit “normal” aging characteristics, whereas CAs from APOE4 mice exhibit “delayed” age related changes in arterial stiffening, which may contribute to elevated cerebral blood flow in Y human and mice carrying the APOE4 allele vs aged matched APOE3.Support or Funding InformationFundingABRC/ADHS18‐205211 (DME, JVE, CJ, TBJ), Biomedical Sciences Program (LJS, RGP, DME), Biomedical Sciences Start‐up Funds (DME)