Force Sensing by Piezo Channels in Cardiovascular Health and Disease

Abstract

Mechanical forces are fundamental in cardiovascular biology, and deciphering the mechanisms by which they act remains a testing frontier in cardiovascular research. Here, we raise awareness of 2 recently discovered proteins, Piezo1 and Piezo2, which assemble as transmembrane triskelions to combine exquisite force sensing with regulated calcium influx. There is emerging evidence for their importance in endothelial shear stress sensing and secretion, NO generation, vascular tone, angiogenesis, atherosclerosis, vascular permeability and remodeling, blood pressure regulation, insulin sensitivity, exercise performance, and baroreceptor reflex, and there are early suggestions of relevance to cardiac fibroblasts and myocytes. Human genetic analysis points to significance in lymphatic disease, anemia, varicose veins, and potentially heart failure, hypertension, aneurysms, and stroke. These channels appear to be versatile force sensors, used creatively to inform various force-sensing situations. We discuss emergent concepts and controversies and suggest that the potential for new important understanding is substantial.

Keywords: anemia; blood pressure; calcium channels; humans; ion channels.

Figure 1.

Primary sequences of human and mouse Piezo1. Shown are single-letter amino acid codes for human Piezo1 (upper line) and mouse Piezo1 (lower line). The sequence alignment was done using Clystal Omega. The regions for which structural data exist for mouse Piezo1 are indicated by olive green background and white lettering (based on the 6B3R structure in the Protein Data Bank: https://www.rcsb.org/pdb). Helical (H) and β-sheet (E) regions are underscored in red and green, respectively. This figure was created using Jalview.

Figure 2.

Piezo1 structure. A, Three-dimensional structure of mouse Piezo1 channel (Protein Data Bank: 6B3R) as seen from the extracellular side. The 3 Piezo1 subunits are shown in orange, purple, and cyan. B, Side view of the same structure. The last 2 helices (37 and 38) of Piezo1 are shown in red and form the ion pore. The blue line demarks the boundaries of the cell membrane. C, Interaction sites between the CED (C-terminal extracellular domain) and transmembrane region. Amino acid residues suggested to form hydrogen bonds or salt bridges are indicated. D, Hydrophobic gate and restriction points in the ion pore.^, Amino acid residues contributing in the central region are shown in green (V2476) and ice blue (L2475), with residues in a cytosolic region in yellow.

Figure 3.

Rapid activation of Piezo1 channels by fluid flow in endothelium. A, Depiction of the experimental arrangement for B and C. Endothelium was freshly isolated from second-order mesenteric artery of adult mouse. A smooth-tipped glass patch pipette was used to create a tight seal on a cell in this endothelium and enable formation of a cell-free excised membrane patch in outside-out configuration so that the outer face of the membrane and channels faced fluid flowing from a pipe. B, Example current recording from a patch as illustrated in (A). Channel opening caused unitary single-channel currents that are shown as flickering downward deflections in dark red. There was spontaneous activity before flow was applied and then flow caused a marked increase in activity, which is shown in greater detail in the expanded trace below in which is seen the closed-channel condition (C) and simultaneous openings of 3 channels (O1, O2, and O3). C, As in B, except the recording was made from endothelium obtained from a mouse in which endothelial Piezo1 had been conditionally deleted at adult stage. No channel activity was seen, suggesting that channel activity in B was mediated by Piezo1 channels. In B, the mouse was a control mouse in which Piezo1 was normal. D, Measurement of membrane potential from freshly isolated endothelium, showing an initial small hyperpolarization in response to flow and then depolarization. The recording was from endothelium obtained from a control mouse. In endothelial Piezo1-deleted mice, there was a small hyperpolarization, but the depolarizing effect of flow was completely absent (these data are not shown here, but they can be found in the study by Rode et al). E, Measurement of blood pressure in conscious mice by telemetry. The mice were either control mice in which Piezo1 was normal (gray symbols) or mice in which endothelial Piezo1 had been conditionally deleted at adult stage (blue symbols). The mice were exercising on a running wheel at the time of the recordings. B–E, Adapted from Rode et al with permission. Copyright ©2017, the Authors.