Peripheral neurovascular link: an overview of interactions and in vitro models

Nerves and blood vessels (BVs) establish extensive arborized networks to innervate tissues and deliver oxygen/metabolic support. Developmental cues direct the formation of these intricate and often overlapping patterns, which reflect close interactions within the peripheral neurovascular system. Besides the mutual dependence to survive and function, nerves and BVs share several receptors and ligands, as well as principles of differentiation, growth and pathfinding. Neurovascular (NV) interactions are maintained in adult life and are essential for certain regenerative mechanisms, such as wound healing. In pathological situations (e.g., type 2 diabetes mellitus), the NV system can be severely perturbed and become dysfunctional. Unwanted neural growth and vascularization are also associated with the progression of some pathologies, such as cancer and endometriosis. In this review, we describe the fundamental NV interactions in development, highlighting the similarities between both networks and wiring mechanisms. We also describe the NV contribution to regenerative processes and potential pathological dysfunctions. Finally, we provide an overview of current in vitro models used to replicate and investigate the NV ecosystem, addressing present limitations and future perspectives.