Piezo 1 and arterial mechanotransduction – PIEZO

Blood vessels experience, sense, and respond to mechanical force. Despite the central physiological importance of arterial mechanotransduction, the molecular identities of the sensors and the signaling pathways involved have long remained elusive. For example, resistance arteries (small diameter) constrict in response to an increase in intraluminal pressure. This physiological pressure-sensitive mechanism, called the myogenic response, allows a constant blood flow despite changes in arterial pressure. In the kidney or the brain, myogenic tone is proposed to play a critical protective role against hypertension-induced injuries. The myogenic tone is inherent to vascular smooth muscle cells (VSMCs) and is independent of the endothelium or the nervous system. This arterial response to pressure is proposed to be initiated by the opening of stretch-activated cationic channels (SAC) present in VSMCs.
Mechanotransduction is also implicated in vascular diseases. For example, a chronic increase in intraluminal pressure (hypertension) induces an adaptive structural rearrangement of resistance arteries. In hypertension, eutrophic inward remodeling significantly contributes to reducing the lumen diameter of arterioles and consequently to increasing peripheral vascular resistance. This arterial remodeling is identified as an important risk factor for cardiovascular events.
How VSMCs are able to sense pressure is only starting to emerge. Very recent findings from the Patapoutian laboratory have provided strong evidence that two novel proteins called Piezo 1 (Fam38A) and Piezo 2 (Fam38B) are essential components of distinct mechanically activated cation channels in mammalian cells. Here, we show preliminary data that Piezo 1 fits the characteristics of the elusive non-selective SAC in arterial myocytes. We hypothesize that Piezo 1 plays a key role in arterial development and function.
We will team up to understand the role of Piezo 1 in arterial mechanotransduction and associated disease states, including hypertension and restenosis. We will take advantage of both a constitutive and a conditional SMCs specific knock-out mouse models to study the role of Piezo 1 in the vasculature. Finally, we will focus on the molecular pathways downstream of Piezo 1 activation in resistance arteries.
These studies will provide insights into the molecular mechanisms of pressure sensing in resistance arteries and will help to define whether Piezo 1 may represent an interesting pharmacological target for the treatment of arterial dysfunction.