Neuropeptide oxytocin facilitates its own brain-to-periphery uptake by regulating blood flow dynamics and permeability

The hypothalamo-neurohypophyseal system is an important neuroendocrine brain-to-blood conduit through which the neurohormones oxytocin and arginine-vasopressin are released from the brain into the general circulation to affect peripheral physiological functions such as salt balance, metabolism and reproduction. However, the mechanism which executes fast and efficient neurohormone release to the periphery remains unsolved. We show, using live imaging in zebrafish, that a hyperosmotic physiological challenge elicits a local increase in neurohypophyseal blood flow velocities and a change in capillary diameter, which is dictated by the geometry of the hypophyseal vascular microcircuit. Genetic ablation of oxytocin neurons and inhibition of oxytocin receptor signaling attenuated changes in capillary blood flow and diameter. Optogenetic stimulation of oxytocin neurons resulted in an oxytocin receptor-dependent increase in blood flow velocities. Lastly, both osmotic challenge and oxytocin neuronal activation elicited a local rise in neurohypophyseal capillary permeability in an oxytocin signaling-dependent manner. Our study demonstrates that physiologically elicited changes in neurohypophyseal blood flow and permeability are regulated by oxytocin. We propose that oxytocin-dependent neuro-vascular coupling facilitates its efficient uptake into the blood circulation, suggesting a self-perpetuating mechanism of peripheral hormone transfer.