PIEZO2 ion channel plays critical role in the formation of coronary vessels and the heart

The ion channel PIEZO2 doesn't just convey touch stimuli. It also plays a key role in the development of coronary vessels, a team led by Annette Hammes from the Max Delbrück Center reports in "Nature Cardiovascular Research." The findings could improve our understanding of congenital heart defects.

Our skin can detect even the slightest breeze. This remarkable sensitivity is thanks to special ion channels embedded in cell membranes that respond to mechanical stimuli. Now a team led by Dr. Annette Hammes, Group Leader of the Molecular Signaling Pathways in Cortical Development lab at the Max Delbrück Center, has shown that one of these channels – PIEZO2 ­– also plays a critical role in the formation of coronary vessels and the heart. Their study was published in Nature Cardiovascular Research.

Several groups at the Max Delbrück Center contributed to the study, including teams led by Professors Gary Lewin, Holger Gerhardt, and Norbert Hübner. "At our center, we bring together a wide range of expertise to understand key biological processes," says Hammes. The new findings could help identify the causes of congenital heart diseases – ultimately allowing earlier diagnosis and treatment. "PIEZO2 might also emerge as a new therapeutic target for cardiovascular disease," she adds.

When coronary vessels malfunction

Dr. Mireia Pampols-Perez, lead author from Hammes' team, used mouse models to demonstrate that coronary arteries do not develop properly without PIEZO2. In the absence of this ion channel, the small vessels either remain too narrow or branch in abnormal ways – reducing oxygen supply to the heart muscle. Similar malformations occurred in mice with an overactive PIEZO2 variant, which in humans causes the rare genetic disorder Marden-Walker syndrome. In both cases, the heart muscle tissue, especially in the left ventricle, becomes thickened – likely due to the aberrant growth of blood vessels.

"Genome-wide association studies suggest that mutations in the PIEZO2 gene may also be linked to cardiovascular conditions in humans, such as heart failure, high blood pressure, or aneurysms," Hammes explains. "Malfunctions in this ion channel during embryonic development may initially lead to subtle yet unnoticeable vascular changes – only to trigger serious heart issues later in life or under physical stress."

PIEZO2 is usually active only during the embryonic stage in endothelial cells that line coronary arteries. After birth, the channel typically shuts down.

However, there is evidence that it may be re-expressed in the adult heart under certain conditions, potentially aiding blood vessel regeneration. This is, of course, an exciting prospect–especially in cases of coronary artery disease or after a heart attack."

Annette Hammes from the Max Delbrück Center 

New options for diagnostics and prevention

To explore whether the PIEZO2 findings from mice also apply to humans, Hammes' team is now collaborating with colleagues from the Helmholtz Institute for Translational AngioCardioScience (HI-TAC) in Heidelberg and Mannheim, and the Max Delbrück Center's Pluripotent Stem Cell Technology Platform. The researchers are using human endothelial cells derived from pluripotent stem cells. "With these models, we aim to determine how PIEZO2 expression and activity can be selectively influenced in humans," says Hammes.

There are many potential medical applications of the research. "This study deepens our understanding of congenital heart defects and expands the list of genes that could be useful in diagnostics and prevention," Hammes explains. "Ultimately, our results could help detect genetically caused cardiovascular diseases earlier – and perhaps even prevent them."