A Novel Rodent Model of Hypertensive Cerebral Small Vessel Disease with White Matter Hyperintensities and Peripheral Oxidative Stress

Abstract

Cerebral small vessel disease (CSVD) is the second most common cause of stroke and a major contributor to dementia. Manifestations of CSVD include cerebral microbleeds, intracerebral hemorrhages (ICH), lacunar infarcts, white matter hyperintensities (WMH) and enlarged perivascular spaces. Chronic hypertensive models have been found to reproduce most key features of the disease. Nevertheless, no animal models have been identified to reflect all different aspects of the human disease. Here, we described a novel model for CSVD using salt-sensitive ‘Sabra’ hypertension-prone rats (SBH/y), which display chronic hypertension and enhanced peripheral oxidative stress. SBH/y rats were either administered deoxycorticosteroid acetate (DOCA) (referred to as SBH/y-DOCA rats) or sham-operated and provided with 1% NaCl in drinking water. Rats underwent neurological assessment and behavioral testing, followed by ex vivo MRI and biochemical and histological analyses. SBH/y-DOCA rats show a neurological decline and cognitive impairment and present multiple cerebrovascular pathologies associated with CSVD, such as ICH, lacunes, enlarged perivascular spaces, blood vessel stenosis, BBB permeability and inflammation. Remarkably, SBH/y-DOCA rats show severe white matter pathology as well as WMH, which are rarely reported in commonly used models. Our model may serve as a novel platform for further understanding the mechanisms underlying CSVD and for testing novel therapeutics.

Mesenchymal Stem Cell-Derived Extracellular Vesicles as Proposed Therapy in a Rat Model of Cerebral Small Vessel Disease

“…Human CSVD is known to involve inflammatory signaling cascade [ 27 ]. Our previous results also established elevated immune brain response in SBH/y-DS [ 23 ]. To further broaden our understanding of the immune involvement in our model, RNA from rat cortices was studied by RNA-sequencing analysis.…”

“…Isoflurane was used for both induction (5%) and maintenance (1.5–2%) of anesthesia. We have previously shown that SBH/y-DS invariably developed hypertension after 1 month that persists as long as the DOCA pellet continues to secrete deoxycorticosterone acetate and NaCl is provided in drinking water [ 23 ]. Sham control animals (“SBH/y sham” group ( n = 11)) were subjected to anesthesia, skin incision and suturing without insertion of the DOCA pellet, and rats were provided tap water with no added salt or potassium.…”

“…We previously described a novel model of CSVD using the salt-sensitive hypertension prone SBH/y rat model, which when salt-loaded with deoxycorticosterone-acetate (DOCA)-salt, incorporates hypertension with peripheral oxidative stress [ 23 ]. In the current study, we investigated the potential therapeutic effect of MSC-EVs in SBH/y rat model of CSVD, while uncovering mechanisms underlying CSVD, and molecular changes induced by MSC-EV treatment.…”

A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia

“…For monogenic SVDs, there are also more reliable models of CADASIL [ 21 ], COL4A1/COL4A2 [ 22 , 23 ], CARASIL [ 24 ], TREX [ 25 ]; and while each might start with a different gene-protein abnormality, the consequences at the glio-vascular unit and for the neuron, are similar – altered basement membranes, inflammation, impaired vascular function and secondary tissue damage. Additional models that explore effects of hypertension and diet in sporadic SVD have been developed [ 26 ].…”

White matter really matters in cerebral small vessel disease

“…Another group proposed to use of deoxy-corticosteroid acetate (DOCA) treated Sabra hypertension prone (SBH/y) rats as a novel model for cSVD. In these animals, the vascular impact of hypertension leading to WMLs and oxidative stress in these animals [163]. In mice, hypertension can be induced by administration of angiotensin II.…”