Mechanotransduction and Uterine Blood Flow in Preeclampsia: The Role of Mechanosensing Piezo 1 Ion Channels

Abstract

There is a large increase in uterine arterial blood flow during normal pregnancy. Structural and cellular adjustments occur in the uterine vasculature during pregnancy to accommodate this increased blood flow through a complex adaptive process that is dependent on multiple coordinated and interactive influences and this process is known as “vascular remodeling.” The etiology of preeclampsia involves aberrant placentation and vascular remodeling leading to reduced uteroplacental perfusion. The placental ischemia leads to development of hypertension and proteinuria in the mother, intrauterine growth restriction, and perinatal death in the fetus. However, the underlying source of the deficient vascular remodeling and the subsequent development of preeclampsia remain to be fully understood. Mechanoreceptors in the vascular system convert mechanical force (shear stress) to biochemical signals and feedback mechanisms. This review focuses on the Piezo 1 channel, a mechanosensitive channel that is sensitive to shear stress in the endothelium; it induces Ca²⁺ entry which is linked to endothelial nitric oxide synthase (eNOS) activation as the mechanoreceptor responsible for uterine vascular dilatation during pregnancy. Here we describe the downstream signaling pathways involved in this process and the possibility of a deficiency in expression of Piezo 1 in preeclampsia leading to the abnormal vascular dysfunction responsible for the pathophysiology of the disease. The Piezo 1 ion channel is expressed in the endothelium and vascular smooth muscle cells (VSMCs) of small-diameter arteries. It plays a role in the structural remodeling of arteries and is involved in mechanotransduction of hemodynamic shear stress by endothelial cells (ECs).

In normal pregnancy, there is a significant increase in uterine artery blood flow and this is necessary for the development of the fetus and maintaining and generating a successful pregnancy outcome (Figure 1).¹ The diameter of the human uterine artery doubles in size in order to accommodate this large increase in blood flow to the feto-placenta unit² and this is accomplished by vasodilation and remodeling of the uterine circulation. The underlying mechanisms that modulate uterine vascular function in pregnancy are currently incompletely understood. Previous studies have focused on uterine vascular remodeling during pregnancy and the effect of blood flow-mediated shear stress on the uterine artery.^3–9

Figure 1.

Change in volume flow during pregnancy. Showing a great rise in uterine arterial blood flow from before pregnancy to near-term. Values are based on those reported by Julian et al.¹

Preeclampsia

Preeclampsia is a condition that usually occurs in the second half of pregnancy—starts at about 20 weeks, during labor or early postpartum. It is characterized by hypertension, proteinuria, and organ dysfunction in the pregnant woman and decline in fetal growth. It affects 3–10% of all pregnancies and contributes to fetal and maternal morbidity and mortality in pregnancy.^10,11 It correlates with increased risk of cardiovascular disease later in maternal life.¹² Preeclampsia is a multisystem disease and its underlying cause is still unknown, though it is known to begin with aberrant placentation, and vascular remodeling. However, the exact mechanism responsible for the aberrant placentation and how it leads to cardiovascular disease remains currently unclear.

Uterine blood flow regulation during pregnancy

During pregnancy, the uterus receives about 5% of total cardiac output and there are 3 parts to the uterine circulation: (i) arteries – arterioles – capillary network – venules – veins; (ii) spiral arteries (which are no longer resistance vessels but large, flaccid conduits) into the intervillous space, now essentially a pool of maternal blood acting functionally as a large capillary network; and (iii) arteries anastomose with veins allowing blood to bypass both the uterine capillary network and the intervillous space.¹³ These arteriovenous anastomoses contribute to the early rise in uterine artery blood flow.

The main source of uterine vascular resistance is the highly muscular spiral arteries. They are the resistance vessels that contract and relax to modulate blood flow in response to changing uterine metabolic needs. During pregnancy, the syncytiotrophoblast invades the endometrium and the cytotrophoblast cells become extravillous trophoblast, which are migratory and nonproliferative cells, invade connective tissues and maternal walls. These extravillous trophoblasts migrate into the spiral arteries and transform them from muscular resistance vessels to wide, flaccid conduits and blood pours into the intervillous space under high pressure.¹⁴ Eradication of the maternal resistance vessels maximizes flow to the placental site but simultaneously limits the vascular control system’s ability to regulate blood flow. This flow becomes a direct function of uterine arterial pressure as predicted by the hemodynamic equivalent of Ohm’s law.¹⁵ This results in a sustained increase in blood flow velocity in the uterine artery which causes an increase in the shear stress on the arterial wall and stimulates the endothelium to increase its production of nitric oxide (NO) and possibly other vasodilators.

Uterine vascular remodeling during pregnancy

Structural and cellular adjustments occur in the uterine vasculature during pregnancy through a complex adaptive process that is dependent on multiple coordinated and interactive influences and this process is known, collectively as “vascular remodeling.” ⁵ These changes include:

• • Medial hypertrophy and hyperplasia⁷;

• • Increases in both venous and arterial diameter and length⁵;

• • Enlargement in arterial caliber with little or no thickening of the vascular wall—except in mice where media thickness increases significantly^6,16,17;

• • Differentiation, proliferation, and elongation of uterine artery smooth muscle cell^3,15; and

• • Increase in protein content of vascular smooth muscle cell (VSMC).¹⁶

These changes serve to adapt the uterine arterial wall to the elevated blood flow required for normal fetal growth and development³ and to prevent uterine artery dysfunction which results in increased vascular resistance impeding blood flow to the fetal-placental unit and limiting fetal growth and development which can lead to health complications later in life.¹⁸

Mechanisms of uterine vascular dilation and functional remodeling in pregnancy

There are several plausible mechanisms for uterine vasodilation to contribute to vascular adaptation in pregnancy:

Myogenic tone.

Given that myogenic tone plays an important role in the regulation of vascular resistance and blood flow to various organs, the decreased myogenic tone and the increased distensibility of resistance-sized uterine arteries are likely to contribute significantly to the adaptation of uterine vascular hemodynamics in pregnancy. Studies have shown in the ovine uterine artery that pressure-induced myogenic tone is regulated through both Ca²⁺ mobilization and Ca²⁺ sensitivity of the contractile process. Pregnancy downregulates myogenic tone of the uterine artery, mediated in part by an increase in the inhibitory effect of extracellular signal-regulated kinase and a decrease in the protein kinase C signaling pathway, which lead to a decrease in Ca²⁺ sensitivity of the myogenic mechanism in the uterine artery during pregnancy¹⁹ but not in preeclampsia, as van Wijk et al. reported an increase in Ca²⁺ sensitivity of the contractile proteins of subcutaneous arteries from preeclamptic women compared to healthy pregnant and nonpregnant women.²⁰ Given that basal Ca²⁺ sensitivity plays a key role in the regulation of myogenic tone and, hence, basal vascular resistance and blood flow, decreased baseline Ca²⁺ sensitivity is likely to play an important role in the adaptation of uterine vascular hemodynamics during pregnancy. The Rho A/Rho kinase signaling may also play a role in the decreased myogenic tone in pregnancy. Goulopoulou et al. observed that pregnancy reduces the contribution of Rho A/Rho kinase signaling pathways to the Thromboxane analog (U-46619)-induced contractions in the uterine arteries.²¹ Other studies in pregnant animals and humans have also reported that the levels of Rho kinase expression and activity are altered by pregnancy in vascular beds.^22,23 In preeclampsia, Rho A/Rho kinase signaling may play a role in the increased Ca²⁺ sensitivity of the contractile proteins of subcutaneous arteries.

Circulating steroids and uterine blood flow

Estrogen, progesterone, and cortisol have an effect on local uterine blood flow through their activity at the level of the endothelium and the smooth muscle in the uterine artery, though the exact mechanism is not yet fully known.²⁴ Increases in uterine artery diameter in humans begin well before placentation is complete, and expansive arterial remodeling can be initiated in rodents by inducing a pseudo-pregnant state in which increases in circulating sex steroids mimic those of pregnancy.⁵ Studies in the ewe²⁵ documented significant but transient increases in uterine blood flow in nonpregnant animals following a single injection of estradiol. Ovarian steroids contribute to uterine arterial enlargement in early pregnancy and also augment the effect of other factors such as shear stress.^25,26 Estrogen, in particular, is a known vasodilator of the uterine circulation.²⁷ The uterine artery has estrogen and progesterone receptors and responds to these steroids via genomic and nongenomic mechanisms.⁵

Increase in circulating levels of vasoactive substances particularly; VEGF, PIGF, and PDGF

During pregnancy, there is a marked increase in circulating levels of vasodilatory and growth-promoting substances, like VEGF, PIGF, and PDGF. Some studies have shown abnormal VEGF, PIGF signaling in preeclamptic women due to overexpression of a soluble receptor for VEGF, PIGF.^2,4,28 Other studies reported abnormally high circulating levels of soluble fms-like tyrosine kinase-1 in preeclampsia and that it contributes to the pathogenesis of the condition.^2,29–31 Although direct evaluation of vascular remodeling was not carried out and the exact mechanism is not known, this is suggestive of a role for VEGF and PIGF in uterine vascular remodeling during pregnancy.

Shear stress and NO

Shear stress has been established as a physiological mechanism for circumferential arterial growth.¹⁵ The hemodynamic adaptation in early pregnancy results in decreased uterine artery impendence and increased blood flow,³² leading to an acceleration of flow velocity and shear stress. The blood vessels dilate when exposed to fluid shear stress which is sensed by the endothelial cells (ECs).¹⁶ Vasodilation and/or vessel growth would allow for the continuation of the increased flow but with a slower velocity thereby normalizing shear stress in the process.⁴ The exact mechanisms by which shear stress leads to circumferential vessel growth and vasodilation have not been completely identified. Earlier reports demonstrated it is as a result of an increase in vascular smooth muscle proteins, particularly the contractile proteins.⁸ Other studies suggest that it is endothelial in origin¹⁵ and a variety of vasorelaxants are released from the ECs including NO which plays a key role in this process^9,33 through a mechanism which involves a rapid but transient increase in intracellular calcium levels and the subsequent activation of endothelial nitric oxide synthase (eNOS) in a Ca²⁺/calmodulin-dependent manner.^34,35 Several studies have provided evidence to support the role of NO in uterine artery remodeling. It was shown that during pregnancy, uterine artery remodeling from eNOS deficient mice is attenuated.³⁶ Also, pregnant rats treated with a NOS inhibitor demonstrated an impairment in the uterine artery remodeling.⁶ Thus, it is a plausible mechanism for uterine arterial enlargement during pregnancy

Pathophysiology of preeclampsia: aberrant maternal uterine vascular remodeling

The uterine vascular remodeling that occurs in normal pregnancy is absent in preeclampsia; cytotrophoblast invasion of the spiral arteries is poor leading to decreased uteroplacental perfusion and consequently preeclampsia. The spiral arteries remain a small resistance vessel. A study of basal plates of placentas of abnormal pregnancies confirmed that the remodeling of the spiral arteries that occurs in normal pregnancy was completely absent in preeclampsia.³⁷ Animal models have been used to study the defective uteroplacental blood flow leading to preeclampsia.^38,39 Although the initiating event is thought to be decreased uteroplacental perfusion as a result of aberrant vascular remodeling, the main cause of this aberrant remodeling is currently unknown, and several factors have been proposed including: environmental, genetic, and immunologic factors.

Placenta ischemia leads to widespread dysfunction of maternal endothelium, activation of vasoconstriction, and development of hypertension. This evidence was provided by a group who studied reduced uterine perfusion pressure rat model to understand the mechanism of reduced uteroplacental perfusion induced development of hypertension and proteinuria associated with preeclampsia.⁴⁰ There is a need to understand and clearly identify the etiology of preeclampsia in order to be able to properly manage the condition and provide better outcomes for both mother and child.

Mechanoreceptors in the vasculature

Mechanoreceptors are found on many cells in almost all systems of the body; they transduce sensory information into intracellular signals. They are present in the vascular system on both the EC membrane and on the VSMC membrane. ECs are constantly exposed to shear stress which is the force per unit area created when blood flow acts on the surface of the internal lining of the blood vessels.⁴¹ Additionally, smooth muscle cells are exposed to stretch resulting from cyclic changes in arterial blood pressure. Mechanotransduction, which is the process through which mechanical forces (shear stress and stretch) is translated to physiological response, is very important for local blood flow control and regulation of vascular tone.⁴²

The structure and function of the endothelium is modified by hemodynamic forces acting on the endothelial lining of the blood vessels. It has been demonstrated in earlier studies that unidirectional, steady laminar shear stress induces changes in the shape of the smooth muscle cells and ECs.⁴³ Other studies have established that shear stress resulting from blood flow initiates a cascade of signaling events in the endothelium and these include: stretch-activated NO production^44–46 to cause vasodilation, vascular remodeling, and angiogenesis.^47–52

Mechanotransduction is the intracellular transmission of the stress or stretch to the conversion of mechanical force to biochemical signals and feedback mechanisms. The process of shear stress mechanotransduction occurs in 4 steps: (i) flow-induced shear stress and stretch; (ii) intracellular transmission of the shear stress and stretch; (iii) conversion of mechanical force to biochemical activity; and (iv) initiation of intracellular signaling and feedback mechanisms (Figure 2). The rapid changes in cellular mechanics during mechanotransduction process are accompanied by long-term gene expression changes.

Figure 2.

Process of shear stress/stretch-induced mechanotransduction in the vasculature.

Mechanoreceptors in uterine blood flow regulation during pregnancy

During pregnancy, there is an increase in blood flow in the uterine arteries which leads to increased shear stress. The ECs lining the arterial wall sense this increase in shear stress and a series of downstream mechanisms are initiated to cause vasodilation. Subsequently, the uterine vasculature undergoes a functional and structural remodeling in order to accommodate the increase in blood flow. Though much is known about the downstream molecular events that mediate flow-dependent dilation, the receptors responsible for transducing the mechanical signal from the flow-induced shear stress remain elusive. This has given rise to various studies of the mechanotransduction process in an attempt to identify the specific mechanoreceptor in the vasculature.

How is the mechanical force converted to biochemical activity?

Several in vitro studies^53–59 have been conducted to study the effects of shear stress on the ECs and the molecular mechanism of mechanotransduction. Two primary components have been proposed: membrane proteins and ion channels.

1. 1. Membrane Proteins: Mechanotransduction occurs on the luminal cell membrane; therefore, membrane proteins are the first candidates for mechanoreception. Possible candidates include: integrin proteins, PECAM, GPCR, and VEGFR.

   • Integrin: Wang and Armant observed that EC integrins are activated by shear stress and they form a clustering association with the adaptor protein Shc which binds with monovalent ligand-mimetic antibody (WOW-1) through a mechanism that involves dynamic and specific interactions between integrins and their endothelial membrane ligands.⁶⁰ Blocking integrin with a specific antibody inhibited shear stress-induced downstream signaling.⁵³ These findings demonstrate that integrin signaling plays a critical role in mechanotransduction of ECs.
   • PECAM-1: PECAM-1 is a transmembrane glycoprotein present on the surface of ECs.⁶¹ It was first proposed to be a candidate mechanoreceptor based on its location at the inter-EC adhesion site which was thought to be the site for mechanotransduction in ECs.⁵⁴ A study in human ECs reported that the tyrosine phosphorylation of PECAM-1 was induced by shear stress. Additionally, the association of PECAM-1 with eNOS was enhanced by shear stress.⁶² Using a SiRNA approach, this study also highlighted the attenuation of shear stress-induced phosphorylation of AKT and eNOS resulting from a downregulation of PECAM-1. Another study reported that PECAM-1 is a mechanoreceptor through a mechanism involving activation of extracellular signal-regulated kinase in the ECs.⁶³ PECAM-1 also regulates Ca²⁺ signal transduction in the EC which is another proposed mechanism of mechanotransduction.⁶⁴ PECAM-1 activation initiates a cation current which is similar to nonspecific cation currents observed in ECs after depletion of calcium stores.⁶⁵ PECAM-1 is also known to activate membrane integrins. Although these findings suggest that PECAM-1 is involved in mechanosensing, it is not a component of cation channels and its exact mechanism of mechanotransduction is not fully known.
   • VEGF receptors: VEGF receptors are membrane proteins that mediate signal transduction across the cell membrane. They regulate the development of the vasculature and undergo biomedical modifications including phosphorylation, oxidation, and proteolysis while carrying out their function. Fetal liver kinase (FLK-1), a specific receptor tyrosine kinase for VEGF and integrins, functions as a mechanosensor in ECs and interacts with Shc.⁶⁶ Shear stress activation of FLK-1 is transient and is not affected by blocking with an anti-VEGF-blocking antibody, whereas blocking Shc-2 attenuates the shear activation of extracellular signal-regulated kinase. Another study⁶⁷ reported that flow-mediated NO production and vasodilation occurs through activation of VEGF2 in ECs. This activation is independent of the VEGF ligand. It has also been reported that VEGFR2 kinase inhibition attenuates flow-induced NO production in the ECs and vasodilation in vivo. These findings suggest that VEGFR2 is a mechanosensor through a mechanism which involves eNOS activation and vasodilation.
   • G-protein-coupled receptors: G-protein-coupled receptors (GPCR) are members of a large family of proteins that function primarily as transducers of extracellular stimuli into intracellular signals. GPCR have been shown to be rapidly activated in ECs exposed to flow-induced shear stress and they link to elevation of [Ca²⁺]_i and NO release.⁶⁸ Evidence also shows that G-proteins mediate the rapid activation of Ras by fluid shear stress in human ECs. These findings suggest a role for GPCR in mechanotransduction.
2. 2. Ion Channels: Stretch-activated ion channels have been described in ECs and it has been suggested that they could be involved in the response to mechanical forces generated by blood flow and pressure.⁵⁶ Other studies proposed that stretch-activated channels are responsible for detection of mechanical stimuli⁶⁹ and the reorientation response to mechanical stress seen in ECs was prevented by chemical inhibitors of these ion channels.⁶⁹ However, the identity and mechanism through which they elicit their response remains unknown. Another study suggested that a K⁺-selective ionic current is involved in the process of mechanotransduction.⁵⁷ Additionally, it has been established that shear stress-induced Ca²⁺ influx activates downstream signaling and this has led to the suggestion that ion channels are responsible for mechanotransduction of shear stress in the ECs.

   • A proposed ion channel has to meet several criteria before it can be considered to be a mechanoreceptor.⁵⁸ First, and most important is that the mechanoreceptor must be a channel to allow rapid influx of ions. Secondly, the mechanoreceptor should be localized in the exact cells and in the appropriate position within the cell membrane. Thirdly, the receptor channel must be necessary for the electrical response of the cell to the mechanical stimulus and not for the subsequent activity of the cell. Fourthly, the receptor must be in a lipid bilayer and be gated by mechanical forces. Removal or blockade of the receptor should eliminate the response.
   • The transient receptor potential (TRP) channels and endothelial function: TRP channels are largely expressed in the cardiovascular system. Studies have shown that the TRP channels mediate a variety of functions in the endothelium including hypoxia sensing, cell migration, barrier function, and release of vasoactive compounds such as NO. In VSMCs, TRP channels mediate Ca²⁺-induced cell proliferation and migration, contraction and stretch, or mechanical sensing.⁷⁰

Importance of Piezo1 channels as mechanoreceptors

The exact mechanism of TRP channels in mechanotransduction remains unclear. As a result of this, new ion channel families, such as the Piezo ion channel family, have been identified and are currently under study to further our understanding of mechanotransduction.⁷¹ Briefly, the Piezo channels are mechanosensitive cation-selective channels. They are large proteins with over 2,000 amino acids.⁷² They are trimers and shaped like a propeller with 3 blades organized around a central pore. This helps to preserve the properties of the channel under various membrane tensions. Activation of Piezo channels generates a cationic nonselective current and the channels are permeable to Na⁺, K⁺, Ca²⁺, and Mg²⁺.

The function of Piezo ion channels in mechanotransduction has been studied by several investigative groups. The channels are expressed in various mechanically sensitive cell types and have been shown to be required for vascular development.⁷³ Piezo1 channels have profound importance for shear stress-evoked Ca²⁺ signaling and nonselective cationic channels in mouse and human endothelial cells.⁷² Piezo1 is required for the development of the mouse vasculature through a mechanism involving mechanotransduction of hemodynamic shear stress by endothelial cells. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells.⁷⁴ Piezo1 signaling has been implicated in red blood cell volume control.⁷⁵ Ranade and his group⁷³ showed that Piezo1 is a critical component of endothelial cell mechanotransduction and is required for embryonic development. Piezo1 is expressed in embryonic endothelial cells and is activated by fluid shear stress and loss of Piezo1 affects the ability of endothelial cells to alter their alignment when subjected to shear stress.⁷⁴ Another study showed Piezo 1 is required for flow-induced ATP release and subsequent P2Y₂/G_q/G₁₁-mediated activation of downstream signaling that results in phosphorylation and activation of AKT and endothelial NOS.⁷⁶ They also found that mice with induced endothelium-specific Piezo 1 deficiency lost the ability to induce NO formation in the endothelium and vasodilation in response to flow and consequently developed hypertension.⁷⁶ Endogenous Piezo 1 channels have been suggested to be direct sensors of shear stress by a study which showed activation by shear stress in excised outside-out cell-free membrane patches.⁷⁷

Piezo 1 as the mechanoreceptor and the regulation of uterine blood flow in pregnancy

A recent study conducted by John et al.⁷⁸ tested the hypothesis that Piezo 1 channel is an important mechanosensor in the uterine circulation during pregnancy (Figure 3). They found that Piezo 1 expression was higher in the endothelial cell layer and VSMCs of late pregnant rats than in nonpregnant rats. Functionally, results from our laboratory (unpublished) show an increase in the concentration-dependent relaxation responses to Piezo 1-specific activator, Yoda 1, in uterine arteries from pseudo-pregnant rats compared to virgin rats which was attenuated by L-NAME (Figure 4). This is consistent with the work of John et al.⁷⁸ who observed greater increases in uterine blood flow to Yoda 1 in pregnant rats compared to nonpregnant rats through a mechanism which involves increases in endothelial cell Ca²⁺ concentration linked to vasodilation via a NO mechanism.

Figure 3.

Summary of the hypothesis that Piezo channels sense changes in blood flow in the uterine artery and mediate vasodilation through influx of Ca²⁺ and activation of Ca²⁺-dependent signaling pathways in the endothelium. Abbreviations: eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

Figure 4.

Yoda 1, a Piezo 1-specific activator, stimulates vasorelaxation in rat uterine arterial rings precontracted with 10 µmol/L Phenylephrine in vitro and this response is inhibited by L-NAME.

What happens in preeclampsia?

Preliminary data from our lab showed that relaxation responses of isolated uterine arteries of hypertensive rats were less than those from normotensive pregnant controls (Figure 5). This is indicative of a downregulation of Piezo 1 channel in preeclampsia. This could be the underlying etiology of the vascular dysfunction which is characteristic of preeclampsia.

Figure 5.

The relaxation response to Yoda 1 in rings from isolated UAs of hypertensive rats was lesser than those from normotensive pregnant controls.

Downstream signaling mechanism

Piezo proteins have large molecular weights and do not conform structurally to other known mammalian proteins or channels.^72,74 This feature has made it difficult to study the mechanism by which the channel senses mechanical stimuli and how they interact with downstream signaling pathways. Another feature of Piezo channels is that when the channels are activated by mechanical stimuli, they mediate immediate increases in currents which decline in even in the presence of the stimulus. This leads to rapid inactivation in a voltage-dependent manner and the molecular mechanism for this inactivation is currently unknown.^79,80 Some studies have been carried out in an attempt to elucidate these mechanisms of Piezo 1 channel action. Gnanasambandam et al. reported that the Piezo 1 channel is permeable to the monovalent cations: K⁺, Na⁺, Cs⁺, and Li⁺ and to the divalent cations: Ba²⁺, Ca²⁺, and Mg²⁺ but it is not permeable to Mn²⁺.⁸¹ As the concentration of these ions increase intracellularly, they stimulate/activate various intracellular signaling pathways. Another study reported that activation of Piezo 1 channel results in an increase in intracellular Ca²⁺ levels stimulating the activity of transglutaminases that cross-link enzymes required for remodeling of small arteries.⁸² Yoda 1 [25 μM] elicits Ca²⁺ flux in Piezo1-transfected cells and it is dependent on extracellular Ca²⁺ as chelation of extracellular Ca²⁺ by addition of EGTA reduced the responses while depletion of intracellular Ca²⁺ stores using Thapsigargin did not have any effect, though Ca²⁺ chelation did not completely abolish the responses.⁸³ Furthermore, concentration-response experiments showed that Yoda1 at micromolar concentrations induced robust Ca²⁺ responses in cells transfected with either human or mouse Piezo1. Cahalan and his team⁷⁵ observed that red blood cells exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression.

Future directions

In preeclampsia, uterine artery dysfunction results in increased vascular resistance, impeding blood flow to the fetal-placental unit and limiting fetal growth and development which can lead to health complications later in life. Therefore understanding the mechanism by which changes in flow of the uterine artery in pregnancy activates Piezo 1 channel-mediated endothelium-dependent vasodilation will pave the way for new insights into understanding the mechanisms of vascular adaptations that occur in the uterine arterial bed during normal pregnancy and clearly identifying the etiology of the aberrant vascular remodeling in preeclampsia. This may lead to a potential breakthrough in finding a cure for the disease, improving pregnancy outcomes and ultimately, later health life.

DISCLOSURE

The authors declared no conflict of interest.