Recurrent endothelin-1 mediated vascular insult leads to cognitive impairment protected by trophic factor pleiotrophin

Vascular dementia (VaD) is a complex neurodegenerative condition, with cerebral small vessel dysfunctions as the central role in its pathogenesis. Given the lack of suitable animal models to study the disease pathogenesis, we developed a mouse model to closely emulate the clinical scenarios of recurrent transient ischemic attacks (TIAs) leading to VaD using vasoconstricting peptide Endothelin-1(ET-1). We observed that administration of ET-1 led to blood-brain barrier (BBB) disruption and detrimental changes in its components, such as endothelial cells and pericytes, along with neuronal loss and synaptic dysfunction, resulting in irreversible memory loss. Further, in our pursuit of understanding potential interventions, we co-administered pleiotrophin (PTN) alongside ET-1 injections. PTN exhibited remarkable efficacy in preserving vital components of the BBB, including endothelial cells and pericytes, thereby restoring BBB integrity, preventing neuronal loss, and enhancing memory function. Our findings give a valuable framework for understanding the detrimental effects of multiple TIAs on brain health and provide a useful animal model to explore VaD's underlying mechanisms further and pave the way for promising therapies.