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

Abstract

Cognitive functions are dependent upon intercommunications between the cellular components of the neurovascular unit (NVU). Vascular risk factors are associated with a more rapid rate of cognitive decline with aging and cerebrovascular diseases magnify both the incidence and the rate of cognitive decline. The causal relationship between vascular risk factors and injury to the NVU is, however, lacking. We hypothesized that vascular risk factors, such as hypertension and dyslipidemia, promote disruption of the NVU leading to early cognitive impairment. We compared brain structure and cerebrovascular functions of 1-year old (middle-aged) male wild-type (WT) and atherosclerotic hypertensive (LDLr −/− :hApoB +/+ , ATX) mice. In addition, mice were subjected, or not, to a transverse aortic constriction (TAC) for 6 weeks to assess the acute impact of an increase in systolic blood pressure on the NVU and cognitive functions. Compared with WT mice, ATX mice prematurely developed cognitive decline associated with cerebral micro-hemorrhages, loss of microvessel density and brain atrophy, cerebral endothelial cell senescence and dysfunction, brain inflammation, and oxidative stress associated with blood-brain barrier leakage and brain hypoperfusion. These data suggest functional disturbances in both vascular and parenchymal components of the NVU. Exposure to TAC-induced systolic hypertension promoted cerebrovascular damage and cognitive decline in WT mice, similar to those observed in sham-operated ATX mice; TAC exacerbated the existing cerebrovascular dysfunctions and cognitive failure in ATX mice. Thus, a hemodynamic stress such as systolic hypertension could initiate the cascade involving cerebrovascular injury and NVU deregulation and lead to cognitive decline, a process accelerated in atherosclerotic mice.

Impact of atherosclerotic disease on cerebral microvasculature and tissue oxygenation in awake LDLR−/−hApoB+/+ transgenic mice

“…Furthermore, confounding effects from other morbidity factors could become too important in 24-month-old ATX mice. In our previous work, 28 where both ATX and WT mice at 12 months of age were used, we observed cognitive differences in the Morris Maze and a decrease in brain perfusion. It was also shown that endothelial dysfunction was already present in ATX mice at 12 months of age when compared with 3-month-old ATX mice.…”

“…They exhibit markedly high concentration of plasma LDL and spontaneously develop atherosclerotic lesions on a chow diet after the age of 6 months. 28,[30][31][32] They were categorized into two age groups: young ATX mice (3-month old) and old ATX mice (12-month old). Our rationale in choosing the cut-off age of 12 months was as follows: ATX mice usually have shorter lifespans than wild type (WT) mice, thus making it difficult to study them at 24 months, which is typically considered to be old age in WT mice.…”

“…Even though capillaries are not anticipated to be directly affected by atherosclerotic lesions because of their simple wall structure, high circulating plasma lipids and proinflammatory factors associated with atherosclerotic disease can still cause deleterious effects on capillary endothelium as discovered in a previous ex vivo study. 28 In the current work, we were interested in the structural and functional changes of cerebral capillaries in an in vivo proatherogenic environment. Using two-photon fluorescence intensity imaging, reference 2-D images were obtained from which multiple capillaries were selected for subsequent two-photon line scans [ Figs.…”

“…25,27 Systemic chronic inflammation caused by atherosclerosis contributes to cerebral endothelial cell senescence and dysfunction, which further leads to blood-brain barrier (BBB) leakage and capillary microbleeding in ATX mice where atherosclerosis is fully developed. 28 The objective of our study was to assess how cerebral hemodynamics, cerebral microvasculature, and cerebral tissue oxygenation were affected by hyperlipidemia-associated atherosclerotic disease. To achieve this goal, multiple optical imaging techniques were used, including ISOI, spectral-domain Doppler OCT, two-photon phosphorescence lifetime microscopy, and line scans with two-photon fluorescence excitation.…”

Review of Alterations in Perlecan-Associated Vascular Risk Factors in Dementia

“…A term that encompasses cognitive decline associated with vascular change is Vascular contributions to Cognitive Impairment and Dementia or VCID. VCID is the second leading cause of dementia [99][100][101] behind Alzheimer's disease (AD) [102][103][104][105] with many of the same vascular risk factors, such as, age, sex, hypertension [106], atherosclerosis, and diabetes mellitus (DM) [107][108][109][110][111][112][113][114]. How metabolic changes such as high glucose, high insulin, or high free fatty acid levels individually or in combination affect perlecan distribution and expression is reviewed in Table 1.…”