Endothelial Dysfunction and Neurovascular Alterations in Autism Spectrum Disorder

The traditional view of autism spectrum disorder (ASD) has largely focused on neuronal mechanisms as the primary drivers of atypical neurodevelopment. However, increasing evidence suggests that vascular and neurovascular processes also contribute to the developmental trajectories associated with the condition. In particular, endothelial cells have emerged as active regulators of brain development through their roles in angiogenesis, blood-brain barrier (BBB) formation, neurovascular signaling, and interactions with the immune system. This chapter examines the growing body of evidence supporting a neurovascular perspective of ASD, in which endothelial dysfunction is considered a biologically meaningful component of pathophysiology rather than a secondary consequence of neural alterations. Evidence from both human studies and experimental models indicates that disturbances in vascular development, BBB integrity, VEGF signaling, endothelial metabolism, and neuroimmune communication can influence brain maturation and behavior. Particular attention is given to prenatal and perinatal factors, including maternal inflammation, placental dysfunction, and environmental exposures that affect endothelial development during critical periods of neurodevelopment. The chapter also explores the contribution of oxidative and nitrosative stress, endothelial adhesion molecules, and the neurovascular unit as mechanisms linking vascular and neural dysfunction. By integrating findings across molecular, cellular, developmental, and systems-level studies, this work advances a framework in which vascular and neural processes are tightly interconnected throughout brain development. This perspective not only provides new insight into the biological heterogeneity of ASD but also highlights the endothelium and the neurovascular unit as promising targets for biomarker discovery and future therapeutic intervention.