Interactions between Notch and MAPK signaling in neurovascular development: Implications for advanced disease modeling and tissue engineering

Neurovascular development is a tightly regulated, highly coordinated process essential for the concurrent growth and patterning of the central nervous system and its vascular network during embryogenesis and early postnatal life. This intricate process relies on dynamic cellular crosstalk that guides the invasion of blood vessels into developing neural tissues, culminating in the establishment of the blood–brain barrier and the regulation of cerebral blood flow. Among the key signaling cascades orchestrating neurovascular development, the Notch and Mitogenactivated Protein Kinase pathways emerge as central regulators of cellular communication, differentiation, and morphogenesis. Recent analyses have underscored a complex interplay between Notch and Mitogen-activated Protein Kinase signaling, revealing that their cooperative and antagonistic interactions are crucial for both normal development and pathological processes. This review synthesizes the current understanding of the molecular mechanisms by which Notch and Mitogen-activated Protein Kinase contribute to neurovascular development and regeneration. Both pathways are modulated by complex feedback mechanisms and extensive crosstalk with other signaling networks, including Wnt and Hedgehog pathways, thereby fine-tuning their influence on neurovascular patterning and repair. Elucidating the integrated roles of Notch and Mitogen-activated Protein Kinase signaling in neurovascular biology not only deepens our understanding of developmental neurobiology but also offers promising avenues for the development of disease models and regenerative therapies. Targeting the interplay between these pathways presents a compelling strategy for therapeutic intervention in neurovascular disorders and in advancing tissue engineering approaches.