The baroreceptor reflex enables the nervous system to sense and respond to changes in blood pressure (BP). These acute responses, in combination with long-term changes in heart rate (HR) and BP, maintain BP homeostasis. Failure of the baroreflex response has adverse cardiorenal consequences; however, the identity of the mechanosensitive baroreceptors is unknown. Investigators now describe two mechanosensitive ion channels — PIEZO1 and PIEZO2 — that are required for baroreceptor activity. “Our study uncovers these two mechanosensitive proteins as key players in BP sensing,” say Ardem Patapoutian and Wei-Zheng Zeng. “Mutations in PIEZO1 and PIEZO2 might therefore be risk factors for baroreflex dysfunction in humans.”

The researchers used retrograde tracing of carotid sensory neurons combined with a sensitive in situ hybridization approach to identify Piezo1 and Piezo2 transcripts in baroreceptor cells. Given that constitutive deletion of Piezo1 and Piezo2 is lethal, the researchers generated mice in which these genes were specifically deleted in vagal neurons. Single Piezo1 and Piezo2 knockout mice showed no phenotype; however, double knockout of Piezo1 and Piezo2 abolished the baroreflex-induced reduction in HR in response to administration of the vasoconstrictor phenylephrine. Double knockout mice also exhibited labile hypertension and had greater BP variability than wild-type mice, consistent with findings in patients with baroreflex failure.

To evaluate the contribution of PIEZO-positive sensory neurons to BP regulation, the researchers manipulated the neural activity of PIEZO2-expressing baroreceptors using an optogenetics approach, showing that stimulation of PIEZO2-sensory neurons induces a baroreflex response with immediate decreases in both BP and HR. “We are interested in understanding how changes in the function of these proteins might affect BP regulation in humans,” explains Patapoutian. “Moreover, our findings open new research avenues to study how neurons decode and process mechanical force information in the vascular system, and to identify new targets for treating hypertension and heart failure.”