The mechanosensitive Piezo1 channels contribute to the arterial medial calcification

Abstract

Vascular calcification (VC) is associated with a number of cardiovascular diseases, as well as chronic kidney disease. The role of smooth muscle cells (SMC) has already been widely explored in VC, as has the role of intracellular Ca2+ in regulating SMC function. Increased intracellular calcium concentration ([Ca2+]i) in vascular SMC has been proposed to stimulate VC. However, the contribution of the non-selective Piezo1 mechanosensitive cation channels to the elevation of [Ca2+]i, and consequently to the process of VC has never been examined. In this work the essential contribution of Piezo1 channels to arterial medial calcification is demonstrated. The presence of Piezo1 was proved on human aortic smooth muscle samples using immunohistochemistry. Quantitative PCR and Western blot analysis confirmed the expression of the channel on the human aortic smooth muscle cell line (HAoSMC). Functional measurements were done on HAoSMC under control and calcifying condition. Calcification was induced by supplementing the growth medium with inorganic phosphate (1.5 mmol/L, pH 7.4) and calcium (CaCl2, 0.6 mmol/L) for 7 days. Measurement of [Ca2+]i using fluorescent Fura-2 dye upon stimulation of Piezo1 channels (either by hypoosmolarity, or Yoda1) demonstrated significantly higher calcium transients in calcified as compared to control HAoSMCs. The expression of mechanosensitive Piezo1 channel is augmented in calcified arterial SMCs leading to a higher calcium influx upon stimulation. Activation of the channel by Yoda1 (10 μmol/L) enhanced calcification of HAoSMCs, while Dooku1, which antagonizes the effect of Yoda1, reduced this amplification. Application of Dooku1 alone inhibited the calcification. Knockdown of Piezo1 by siRNA suppressed the calcification evoked by Yoda1 under calcifying conditions. Our results demonstrate the pivotal role of Piezo1 channels in arterial medial calcification.

Activation of Piezo1 promotes osteogenic differentiation of aortic valve interstitial cell through YAP-dependent glutaminolysis

“…It was reported that Dooku1 selectively inhibited the endogenous Piezo1 channel and Yoda1-induced dilation in aorta (39). Recent study has also found that application of Dooku1 could inhibit arterial medial calcification (40). Therefore, we chose Dooku1 as a useful tool for in vivo study.…”

The Role of the Piezo1 Mechanosensitive Channel in the Musculoskeletal System

“…Dooku1, a Yoda1 analogue without agonistic effect, reversibly antagonizes Yoda1 activation [ 80 ]. Although, according to the original concept, Dooku1 has an inhibitory effect only on channels activated by Yoda1, several studies report that an antagonistic effect was also observed in the case of constitutively active channels [ 6 , 80 , 81 ]. It is worth mentioning how open Piezo1 channels can be considered constitutively active due to the influence of cells on each other in tissues compared to the measurements performed on individual, isolated cells.…”

“…Therefore, articles discussing the role of Piezo channels in different cell types, tissues, and organs both under physiological and pathological conditions follow one another. A significant amount of scientific data is available about the fundamental role of the Piezo1 channel in the development and function of the cardiovascular system [ 2 , 3 , 4 , 5 , 6 ], in the functioning of the pancreas [ 7 ] and the excretory organ system [ 5 ], in the homeostasis of epithelial cells [ 8 , 9 , 10 , 11 ], in innate immunity [ 12 ], as well as in the responses of blood cells to mechanical stimuli [ 13 ]. Although the number of studies related to the locomotor system has increased significantly in recent years, the role of Piezo1 channels in these organs is still far from being precisely clarified.…”

Mitochondria spatially and temporally modulate VSMC phenotypes via interacting with cytoskeleton in cardiovascular diseases

“…High shear stress induces expression and activity of Piezo1 upregulation[ 139 ]. And Piezo1 is highly expressed in aortic stiffening tissues or calcifying condition [ 140 , 141 ]. Augmented Piezo1 channel expression [ 140 ], paralleling with Piezo1 activation lead to [Ca 2+ ]i dramatically elevated via Ca 2+ released from mitochondria [ 142 ].…”

“…And Piezo1 is highly expressed in aortic stiffening tissues or calcifying condition [ 140 , 141 ]. Augmented Piezo1 channel expression [ 140 ], paralleling with Piezo1 activation lead to [Ca 2+ ]i dramatically elevated via Ca 2+ released from mitochondria [ 142 ]. Then increased [Ca 2+ ]i induces arteries remodeling [ 143 ].…”