Animal Models of Vascular Cognitive Impairment and Dementia (VCID)

Abstract

Although SHRSP develop severe hypertension, milder chronic hypertension is induced by supplementing drinking water with the NOS-inhibitor L-N-Nitroarginine methyl ester, 39 or chronic infusion of angiotensin II by minipump. 40 Mice receiving a subpressor infusion of angiotensin II develop mild hypertension (mean arterial blood pressure 90 mm Hg, relative to 70 mm Hg in saline-infused controls). 40 In addition to vascular actions, subpressor concentrations of the hyper-tensive agent may have direct effects on neural organization and metabolism. Hyperhomocysteinemia in Mice and Rats Elevated plasma concentration of the nonessential amino acid homocysteine, termed hyperhomocysteinemia, is a risk factor for VCID. 41 In wild-type mice, a diet deficient in 3 B vitamins (B6, B9-folate, and B12) resulted in hyperhomocysteinemia within 10 weeks, accompanied by reduced capillary density in brain tissue and impaired performance in Morris water maze.

Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

“…Animal models of chronic cerebral hypoperfusion are used as subcortical VCI models and do not fully explain all aspects of VCI in humans. VCI also results from cardiovascular mechanisms such as heart failure, hypertension, cardiac arrythmia, arterial sclerosis, cerebral amyloid angiopathy, transient ischemia, focal ischemia, embolism, and hereditary vasculopathy (e.g., CADASIL) [8,17,18]. 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.…”

“…VCI results from systemic, cardiac, or local large or small vessel disease [5,6]. There are several causes of VCI: cerebral small vessel disease, multi-infarct dementia; strategic infarct (i.e., located in a functionally-critical brain area), hemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy), severe hypoperfusion (e.g., heart failure, cardiac arrhythmia), and hereditary vasculopathy (e.g., cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL) [7,8]. No single animal model can replicate them all [9].…”

Therapeutic Strategies and Drug Development for Vascular Cognitive Impairment

“…There is no clear consensus on the most promising molecular target: recent studies have investigated diverse pathophysiological mechanisms including vascular oxidative stress, inflammation, immune trafficking, blood–brain barrier permeability, vascular beta‐amyloid, neurovascular signaling, trophic coupling, perivascular and vascular solute clearance, and others . Animal models have been developed that reproduce specific aspects of human VCI syndromes and diseases including chronic forebrain ischemia, chronic hypertension, and cerebral amyloid angiopathy . These models are being used to screen drugs for beneficial effects.…”

Structural and functional brain alterations in a murine model of Angiotensin II‐induced hypertension

“…) animal models are generated by either (i) the induction of local and global hypoperfusion, (ii) genetic modifications, or (iii) chronic hypertension (AngII) (Venkat et al . ; Gooch and Wilcock ; Helman and Murphy ). Hypoperfusion models generally lack satisfactory reproducibility of human cSVD as they often result in infarcts and vascular remodeling only distributed to distinct vascular regions.…”

“…Instead, we find a large variety of animal models that try to mimic disease conditions and outcomes as close as possible to human findings. Specifically for cSVD, the most common cause of VaD (Huijts et al 2013(Huijts et al , 2014Yamashiro et al 2014) animal models are generated by either (i) the induction of local and global hypoperfusion, (ii) genetic modifications, or (iii) chronic hypertension (AngII) (Venkat et al 2015;Gooch and Wilcock 2016;Helman and Murphy 2016). Hypoperfusion models generally lack satisfactory reproducibility of human cSVD as they often result in infarcts and vascular remodeling only distributed to distinct vascular regions.…”