Coordinated interaction of the vascular and nervous systems: from molecule- to cell-based approaches.

Endothelial cells (ECs) build blood vessels and regulate their plasticity in coordination with neurons. Likewise, neurons construct nerves and regulate their circuits in coordination with ECs. Blood vessel/nerve interactions, ultimately, play essential roles for the neurovascular network and brain function. With conventional molecular approaches, such coordinated interaction is likely due to complex interplay of neuroangiogenic factors and receptors. Aside from molecular regulation of neuroangiogenic factors, currently, cell-based approaches to investigate how blood vessels (or nerves) respond to nerves (or blood vessels) appropriately in the pathophysiological situation are gradually emerging. In order to define responsiveness and flexibility of the neurovascular network in response to the local need, the intercellular communication and coordinated interaction between the vascular and nervous systems need to be thought as a working unit. Based on the scale of the working unit which is in the millimeter range with respect to the physical distance of the neurovascular network, we propose to use a rather conceptual term "Millibiology". The millibiological approach for the coordinated interaction might bring us new paradigm to define neurovascular functions in the pathophysiological state.