*4.6. Improved Vascular Profile in 3xTg-AD Survivor Females*

Hypertension is a risk factor to develop cognitive impairment and dementia [66] and is associated with the pathological manifestations of Alzheimer's disease [67]. Although it is more prevalent in men, a recent study demonstrated that midlife hypertension increases the risk of dementia in women but not in males [68]. Arterial pressure increases in a sexand age-specific manner similar to humans, showing sex differences until 14 months [69]. In agreement with this, the sex effect was observed in this study, with males presenting an increased systolic blood pressure. Although our results did not demonstrate a higher systolic blood pressure in 3xTg-AD mice than NTg mice, as it has been observed in AβPP/PS1 mice [70], a correlation between higher levels of systolic blood pressure and decreased regional cerebral blood flow was observed in 3xTg-AD mice.

AD is associated with cerebral and peripheral artery dysfunction, a process that can lead to altered blood flow to the brain, which in turn can increase the risk of developing AD or impair AD pathology [71,72]. In mice models of AD disease, both peripheral large [18–20] and small [21] artery dysfunction have been reported. A previous study showed decreased AChand sodium-nitroprusside-dependent relaxations in conjunction with increased endothelin-1 contractions in aortas from 11-month-old male 3xTg-AD mice [18]. Consistently, in the 16 month-old male 3xTg-AD compared to NTg mice of the present study, similar low levels of ACh-induced relaxations, impairments of sodium nitroprusside responses, and enhanced contractions to KCl 100 mM were observed. Notably, 3xTg-AD female mice survivors had an improved vascular profile.

On the one hand, although 3xTg-AD females showed similar low levels of ACh relaxation than males, relaxations to sodium nitroprusside and contractions to KCl were unaltered compared to NTg mice. On the other hand, the angiogenic growth capacity of the MCA and aorta was higher in 3xTg-AD compared to NTg females, and 3xTg-AD females showed greater aortic angiogenesis than 3xTg-AD males. In a precedent work, the anxiouslike behavioral profile correlated with vascular alterations in small mesenteric arteries from 15-month-old 3xTg-AD female mice [21]. Altogether, we suggest that the vascular profile is tightly linked to the overall health status, especially in female 3xTg-AD mice.

The increased angiogenic response correlated with increased CBF in the cortex and hippocampus in 3xTg-AD compared to NTg females, an effect that is consistent with the concept that angiogenesis, would be a compensatory response to impaired CBF in AD [22]. These findings agree with previous studies that found increased angiogenesis in the hippocampus, midfrontal cortex, substantia nigra, pars compacta, and locus ceruleus of post mortem human AD brains [73]. It is worth noting that increased angiogenesis, which has been associated with the presence of Aβ [24,74–76], could be linked to increased vascular permeability, especially under pro-oxidant and pro-inflammatory environments, such as in AD [23,24]. A non-invasive method was used to measure blood pressure due to the old age of mice. However, a high-fidelity blood pressure phenotyping method (e.g., radiotelemetry) would be necessary to confirm blood pressure data. Besides, we used the thoracic aorta (i.e., a large conductance artery) as a model for generic peripheral artery function. Therefore, the present study is limited by the lack of information on vascular function in peripheral resistance arteries, which might reflect better what happens at the level of cerebral vasculature.
