Adult mice expressing hAPOE4 demonstrated significantly reduced phenylephrine-induced contractions, acetylcholine-induced relaxation, and force development per unit stretch compared to hAPOE3 mice.
Adult mice homozygous for hAPOE4 exhibit subtle functional and structural differences in the descending thoracic aorta compared to hAPOE3 mice, which may contribute to the increased cardiovascular risk observed in APOE4 carriers.
Introduction: Our previous studies showed allele-related changes in vascular reactivity in the left common carotid artery of adult male and female mice expressing the human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)MaeN8) and APOE4 (B6.129P2-Apoetm2(APOE*4)MaeN8). As different vascular structures have different functions, we hypothesize that the descending thoracic aorta (dTA) might also exhibit allelotype-related changes, which could predispose these mice to adverse cardiovascular (CV) outcomes. Methods: To test our hypothesis, we isolated the dTA from 6.8±0.2-month-old male and female mice expressing hAPOE3 (n=6) or hAPOE4 (n=6). For each experiment, four consecutive aortic segments (2 mm each) were isolated and used for myography. The segment most proximal to the aortic arch was designated S1, with the most distal designated S4. We evaluated vascular reactivity by measuring constriction responses to potassium (K+, 60mM) and phenylephrine (PE, 0.01µM –100µM). Endothelium-dependent vasodilation was assessed using acetylcholine (ACh, 0.01µM – 100µM). Additionally, we examined mechanical properties by constructing length-tension curves to assess the relative contributions of elastin and collagen. Data were analyzed using Student’s t-test, and nonlinear curve fitting. Values were considered statistically significant at p< 0.05 and are reported as mean ± SEM. Results: Our study demonstrated segmental heterogeneity along the descending TA in both APOE3 and APOE4 mice. However, PE-induced contractions in S1 aortic rings of the dTA were significantly greater in the APOE3 mice compared to the APOE4 mice. Furthermore, ACh-induced relaxation in S4 aortic rings was greater at higher concentrations in APOE3 mice compared to that of APOE4 mice. K+-induced contractions were similar in APOE3 and APOE4 mice. Finally, length-tension relationships in S1 aortic segments from APOE3 mice exhibited a small yet significantly greater force development per unit stretch than those in S1 segments from APOE4 mice. Conclusions: Although the specific mechanisms remain unclear, carrying the APOE4 allele has been linked to a higher risk of cardiovascular disease. Our data show subtle functional and structural differences in descending thoracic aorta segments from adult mice homozygous for hAPOE4 compared with those homozygous for hAPOE3. These differences may also persist with aging and could contribute to the vascular pathology observed in APOE4 carriers. Funding: ABRC/ADHS18-205211 (DME, CBJ), Arizona Alzheimer’s Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636), and matching funds from Midwestern University (DME), Biomedical Sciences Program (SJ, DME), CGS Intramural support (DME, CBJ), and Biomedical Sciences Start-up Funds (DME). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Jovkovic et al. (2026) studied Cardiovascular risk in APOE4 carriers (n=12). hAPOE4 expression vs. hAPOE3 expression was evaluated on Vascular reactivity and mechanical properties of the descending thoracic aorta. Adult mice expressing hAPOE4 demonstrated significantly reduced phenylephrine-induced contractions, acetylcholine-induced relaxation, and force development per unit stretch compared to hAPOE3 mice.