Vascular dementia (VaD) is the second most common cause of dementia and leads to a decline in cognitive thinking via conditions that lead to blockage or reduced blood flow to the brain. It is a poorly understood disease, and the changes that occur are often linked to other types of dementia such as Alzheimer's disease. To date, there are no approved therapies or drugs to treat the symptoms of VaD, even though there is some evidence of drugs approved for Alzheimer's that might have some benefit in patients diagnosed with VaD. The altered blood flow that precedes VaD may result in compensatory mechanisms, such as angiogenesis, to increase blood flow in the brain. Angiogenesis, the process of new blood vessel formations from pre-existing ones, involves several pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and is regulated by a variety of growth factors from neurons, astrocytes, and pericytes in the brain as well the extracellular matrix (ECM). The ECM highly regulates angiogenesis and other processes in the brain. One such ECM component is the heparan sulfate proteoglycan perlecan and its bioactive region, Domain V (DV). Here we discuss the potential role of DV as a novel therapy to treat VaD.