Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains.

Vascular myocytes are central to brain aging. Small vessel disease (SVD; arteriolosclerosis) is a widespread cause of lacunar stroke and vascular dementia and is characterized by fibrosis and depletion of vascular myocytes in small penetrating arteries. Vascular endothelial growth factor (VEGF) is associated with brain aging, and Immunolabeling for vascular endothelial growth factor receptor 2 (VEGFR2) is a potent determinant of cell fate. Here, we tested whether VEGFR2 in vascular myocytes is associated with older age and SVD in human brain. Immunolabeling for VEGFR2 in deep gray matter was assessed in older people with or without moderate-severe SVD or in younger people without brain pathology or with a monogenic form of SVD (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). All cases were without Alzheimer's disease pathology. Myocyte VEGFR2 was associated with increasing age (p = 0.0026) but not with SVD pathology or with sclerotic index or blood vessel density. We conclude that VEGFR2 is consistently expressed in small artery myocytes of older people and may mediate effects of VEGF on brain vascular aging.

Experimental models of vascular dementia and vascular cognitive impairment: a systematic review.

Vascular cognitive impairment (VCI) encompasses vascular dementia and is the second most common cause of dementing illness after Alzheimer's disease. The main causes of VCI are: cerebral small vessel disease; multi-infarct dementia; strategic infarct (i.e. located in a functionally-critical brain area); haemorrhage/microbleed; angiopathy (including cerebral amyloid angiopathy); severe hypoperfusion (e.g. cardiac arrhythmia); and hereditary vasculopathy (e.g. cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL). In this systematic analysis, we aimed to relate cognitive and neuropathological features of experimental models to clinical VCI. We extracted data from 107 studies covering 16 models. These included: brief global ischaemic insults (in rats, mice or gerbils); chronic global hypoperfusion (rats, mice, gerbils); chronic hypertension (in primates or stroke-prone, spontaneously-hypertensive rats); multiple ischaemic lesions because of intra-vascular emboli (in rodents, rabbits or primates); strategic ischaemic lesions (in rats or mini-pigs); generalised vasculopathies, because of mutant Notch3, hyperhomocysteinaemia, experimental diabetes mellitus or lack of cerebral vasodilator M(5) receptors (rats or mice). Most cognitive testing showed deficits in working and reference memory. The lesions observed were microinfarcts, diffuse white matter lesions, hippocampal neuronal death, focal ischaemic lesions and micro-haemorrhages. The most-used model was bilateral carotid artery occlusion in rats, leading to chronic hypoperfusion and white matter injury.