Watch Out for the Piezo2 Link to Orthostasis: Is There a More Complex Ultrafast Body-Wide Piezo2 System Operational?

Several underlying protective mechanisms have been identified, yet orthostatic hypotension, a sudden decrease in systemic blood pressure upon standing) can frequently occur, especially with aging. The very initial step leading to a cascade of events preventing orthostatic hypotension, and perhaps responsible for orthostatic hypotension, is still under investigation. PIEZO2 in vagal ganglia has been shown to contribute to cardiovascular stability by preventing orthostatic hypotension in a time-locked and fine-tuned way to atrial and ventricular systole. Accordingly, a distinct group of vagal neurons with end-net endings in the heart initiate a blood-volume-dependent reflex in response to decreased filling of the heart to compensate for upright posture and hemorrhage. This robust feedback control contributes to counterbalance the impact of gravity in order to serve cardiovascular stability. The current perspective manuscript is aiming to highlight that this finding is only one side of a coin, if we consider an underlying novel ultrafast body-wide Piezo2 system, underpinned by the principally Piezo2-coupled autonomic nervous and proprioceptive systems, and the Piezo2-initiated ultradian ultrafast non-synaptic signaling of the heart-brain and muscle-brain axes. The knockout/ablation of PIEZO2 in vagal ganglia not only critically targets this novel complex body-wide Piezo2 mechanism, but it highlights Piezo2’s crucial importance with system-wide relevance by mimicking acquired Piezo2 channelopathy or quasi Piezo2 channelopathy (loss of function).