High Systolic Blood Pressure Induces Cerebral Microvascular Endothelial Dysfunction, Neurovascular Unit Damage, and Cognitive Decline in Mice

Abstract

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction–induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

A Pilot Study Investigating Changes in Capillary Hemodynamics and Its Modulation by Exercise in the APP-PS1 Alzheimer Mouse Model

“…Experiments were performed in male wild-type mice at 6 months old (WT6: n = 4), transgenic Amyloid Precursor Protein Presenilin-1 (APP/PS1) mice at 6 months old (AD6: n = 4), and APP/PS1 mice at 6 months old for which voluntary exercise was initiated at 3 months old (AD6&EX: n = 4). Previous work showed a clear onset of cognitive symptoms in APP/PS1 mice at 4.5 months old (Cifuentes et al, 2015) and established at 6 months old (de Montgolfier et al, 2019), and thus, we conducted imaging at 6 months old and investigated the hemodynamic changes in this relatively early stage of AD. For the AD6&EX group, exercise was voluntary.…”

Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

“…For instance, animal models of chronic cerebral hypoperfusion show white matter lesions and cognitive impairment, but do not correspond well to the cardiovascular mechanisms of VCI. To make up for this drawback, animal models of cardiovascular diseases such as heart failure (transverse aortic constriction model [21][22][23][24], myocardial infarction model [25]), hypertension (stroke prone spontaneously hypertensive rat model [26,27], chronically hypertensive rhesus monkey model [28]), atherosclerosis (Apolipoprotein E knockout mouse model [29,30], low-density lipoprotein receptor-knockout mouse model [31]), and embolic models [32,33] are essential for a deeper understanding of vascular dementia in humans [17,18]. Figure 1.…”

Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr−/−:hApoB+/+ mice

“…Epidemiological studies in individuals with AD or in the elderly identified vascular complications associated with peripheral or brain diseases as risk factors for AD (Breteler 2000;de la Torre 2002). Altogether, this suggests that cognitive decline may be unveiled by brain vascular abnormalities and in particular brain microvascular abnormalities (de la Torre 2002;de Montgolfier et al 2019;Zlokovic 2002).…”