Abstract Body: Background: Currently, mouse aortic aneurysm studies are conducted at room temperature (RT, 20-22 °C). However, thermoneutrality (TN), with temperature at ~30 °C, is the ambient temperature at which energy expenditure maintains basal metabolic rate in mice. This study aimed to determine the impact of TN relative to RT on angiotensin II (AngII)-induced aortic aneurysm development in hypercholesterolemic mice.

Methods: Three hypercholesterolemic mouse models were used to assess the effects of TN on aortic rupture and aortic aneurysm development: Apoe^-/- mice fed a normal laboratory diet, Ldlr ^-/- mice fed a Western diet, and C57BL/6J mice infected with adeno-associated viruses (AAVs) containing a mouse PCSK9 gain-of-function mutation (AAV.mPCSK9D377Y) and fed a Western diet. Male mice of the 3 mouse strains at 8 to 10-week-old were implanted with mini osmotic pumps subcutaneously to infuse either saline or AngII (1,000 ng/kg/min) for 4 weeks. During the infusion period, mice were housed at either 20 °C (RT) or 30°C (TN). The primary endpoint was ex vivo aortic diameters of the suprarenal aortic region.

Results: Despite body weights not differing between the two groups across the three hypercholesterolemic mouse models, mice housed at TN exhibited whitening of brown adipose tissue and significantly downregulated mRNA abundance of Ucp1, Pgc1α, Prdm16, Dio2, and Cidea compared to those housed at RT, regardless of infusion with either saline or AngII. Plasma total cholesterol concentrations were similar between the two groups within each mouse model. The mortality rate, caused by either ascending or abdominal aortic rupture, was comparable between RT and TN groups within each mouse model. The maximum diameters of ascending aortas were not different between the RT and TN groups [Apoe ^-/- mice: 1.89± 0.08 mm vs 1.71 ± 0.04 mm, P = 0.07; Ldlr ^-/- mice: 1.70 ± 0.04 mm vs1.86 ± 0.04 mm, P = 0.19; mPCSK9(D377Y)-AAV injected mice: 1.39 ± 0.04 mm vs 1.46 ± 0.07 mm, P = 0.38]. Maximal diameters of abdominal aortas were also not different between the two groups [Apoe ^-/- mice: 1.05 (0.96-1.68) mm vs 0.98 (0.92-1.05) mm, P = 0.27; Ldlr ^-/- mice: 1.29 (0.84-2.65) mm vs 1.60 (1.60-1.86) mm, P = 0.75; mPCSK9(D377Y)-AAV injected mice: 1.37 (0.90-2.21) mm vs 1.58 (1.26-2.75) mm].

Conclusion: Thermoneutrality during 4 weeks of AngII infusion did not influence formation of aortic aneurysms in hypercholesterolemic mice.