Interpericyte tunneling nanotubes regulate neurovascular coupling
Signaling between cells in the neurovascular unit, or neurovascular coupling, is essential for matching local blood flow to neuronal activity. Pericytes interact with endothelial cells and extend the processes that envelop capillaries, covering up to 90% of their surface1,2. Pericytes are candidates for regulating microcirculatory blood flow because they are strategically positioned along capillaries, contain contractile proteins, and respond rapidly to neuronal stimulation3,4, but it was unclear whether they synchronize microvascular dynamics and neurovascular coupling within a capillary network. Here, we identify nanotube-like processes that connect two bona fide pericytes on distinct capillary systems, forming a functional network in the mouse retina, which we named interpericyte tunneling nanotubes (IP-TNTs). We demonstrate that the latter (i) have an open proximal side and a closed terminal that connects to distal pericytic processes via gap junctions, (ii) transport organelles, including mitochondria, which can move along these processes, and (iii) serve as conduits for intercellular Ca2+ waves, thus ensuring communication between pericytes. Using live two-photon microscopy imaging, we demonstrate that retinal pericytes rely on TNT-IPs to control local neurovascular coupling and coordinate light-evoked responses between adjacent capillaries. IP-TNT damage after ablation or ischemia disrupts intercellular Ca2+ waves, impairing blood flow regulation and neurovascular coupling. Notably, pharmacological blockade of Ca2+ influx preserves TNT-IPs, rescues light-evoked capillary responses, and restores blood flow after reperfusion. Our study thus defines IP-TNTs and characterizes their critical role in the regulation of neurovascular coupling in the living retina under physiological and pathological conditions.
