Variability in vascular smooth muscle cell stretch-induced responses in 2D culture
Received: 14 April 2015 | Accepted: 12 August 2015 | Published: 21 August 2015
Vascular Cell ISSN: 2045-824X
The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to mechanical stress, in the form of circumferential and longitudinal stretch. Cyclic stretch evokes VSMC proliferation, apoptosis, phenotypic switching, migration, alignment, and vascular remodeling. Given that these responses have been observed in many cardiovascular diseases, a defined understanding of their underlying mechanisms may provide critical insight into the pathophysiology of cardiovascular derangements. Cyclic stretch-triggered VSMC responses and their effector mechanisms have been studied
Vascular smooth muscle cells (VSMCs), in addition to endothelial cells (ECs) and fibroblasts, are one of the three main cell types that compose the blood vessel wall [1, 2]. VSMCs, found in the tunica media, are terminally undifferentiated cells, in that they alter their phenotype based on the surrounding microenvironment. In healthy adult blood vessels, SMCs generally display a contractile, or differentiated, phenotype, characterized by a slow rate of proliferation and the expression of contractile, or smooth muscle cell, markers. These markers include calponin, smooth muscle (SM) alpha actin, SM myosin heavy chain (MHC), and SM22 [3–5]. The expression of these contractile markers is largely regulated by the dimerization and binding of the transcription factor serum response factor (SRF) to CArG elements in the promoter regions of smooth muscle cell-specific genes [4–10]. The contractile nature of VSMCs allows them to regulate myogenic tone, blood pressure, and blood flow within the blood vessel . Conversely, in the context of vascular injury, VSMCs often switch from a contractile to synthetic, or undifferentiated, phenotype, which is characterized by a decrease in the expression of contractile markers. Moreover, synthetic VSMCs display increased rates of VSMC proliferation, migration and extracellular matrix (ECM) remodeling [3–5].
Blood pressure is largely responsible for mechanical stress on the blood vessel wall. During systole, the vessel, and consequently, the VSMCs, experience both longitudinal and circumferential stretch . Under physiological conditions, the aorta undergoes about 10 % circumferential strain during systole . This number increases to about 20 % in conditions of hypertension [12, 13]. The pulsatile nature of blood flow exposes the VSMCs in blood vessels to cyclic mechanical stretch. The elasticity of blood vessels allows them to counteract the perpendicular and longitudinal forces exerted by increases in blood pressure [1, 12]. To adapt to increases in blood pressure, blood vessels undergo vascular remodeling, which encompasses changes in VSMC and EC migration, proliferation and apoptosis, as well as turnover of ECM proteins, to increase their rigidity [1, 2]. This remodeling contributes to the pathogenesis of many vascular diseases.
This review will focus mainly on VSMC responses under
The effects of cyclic stretch on VSMCs and their associated mechanisms have widely studied
|Zhu [||AoSMC (human)||1 Hz||STREX||10 %||Collagen I||Uniaxial||0–3 h||Alignment ↑|
|Liu [||AoSMC (rat)||0.5–2 Hz||FX-4000||10 %||Collagen I||Equibiaxial||0–12 h||Alignment ↑|
|Chen [||AoSMC (bovine)||1 Hz||FX-4000||10 %||Collagen I||24 h, 48 h||Sinusoidal||Alignment ↑|
|Standley [||AoSMC (rat)||1 Hz||Flexercell||20 %||Collagen I||Uniaxial||48 h||Alignment ↑|
|Li [||AoSMC (bovine)||1 Hz||FX-4000||10 %||Collagen I||0–24 h||Square||Alignment ↑|
|Standley [||AoSMC (rat)||1 Hz||Flexercell||20 %||Collagen I||Uniaxial||48 h||Proliferation ↑|
|Li [||AoSMC (bovine)||1 Hz||FX-4000||10 %||Collagen I||0–24 h||Square||Proliferation ↑|
|Chahine [||AoSMC (rabbit)||1 Hz||FX-4000||20 %||48 h||Proliferation ↑|
|Chang [||AoSMC (rat)||1 Hz||FX-2000||20 %||0–24 h||Sinusoidal||Proliferation ↑|
|Liu [||AoSMC (rat)||1 Hz||Flexercell||5 %, 15 %||Collagen I||2 h||Proliferation ↑|
|Liu [||AoSMC (mouse)||1 Hz||FX-3000||0–25 %||0–60 min||Proliferation ↑|
|Mata-Greenwood [||PASMC (sheep)||1 Hz||FX-4000||20 %||Collagen I||Biaxial||0–24 h||Proliferation ↑|
|Song [||Venous VSMC (rat)||1 Hz||Custom||0–24 h||Proliferation ↑|
|Song [||AoSMC (human)||1 Hz||FX-5000||10 %, 16 %||Collagen I||0–24 h||Proliferation ↑|
|Morrow [||VSMC (rat)||1 Hz||FX-4000||0–15 %||0–24 h||Heart(P)||Proliferation ↓|
|Guha [||VSMC (rat)||1 Hz||FX-4000||0–10 %||Pronectin||0–24 h||Heart(P)||Proliferation ↓|
|Cheng [||AoSMC (human)||1 Hz||FX-2000||20 %||Collagen I||0–24 h||Sinusoidal||Apoptosis ↑|
|Su [||Portal vein VSMC (swine)||1 Hz||FX-4000||10 %||Laminin||24 h||Apoptosis ↑|
|Sotoudeh [||VSMC (porcine)||1 Hz||Custom||7 %, 25 %||Equibiaxial||0–48 h||Sinusoidal||Apoptosis ↑|
|Wernig [||VSMC (rat)||1 Hz||FX-4000||7 %, 15 %||Collagen I||0–60 min||Apoptosis ↑|
|Song [||AoSMC (human)||1 Hz||FX-5000||10 %, 16 %||Collagen I||0–24 h||Apoptosis ↑|
|Morrow [||VSMC (rat)||1 Hz||FX-4000||0–15 %||0–24 h||Heart(P)||Apoptosis ↑|
|Guha [||VSMC (rat)||1 Hz||FX-4000||0–10 %||Pronectin||0–24 h||Heart(P)||Apoptosis ↑|
|Yao [||AoSMC (rat)||1.25 Hz||FX-4000||10 %||Gelatin||Equibiaxial||24 h||Differentiation ↑|
|Turczynska [||Mouse portal vein||0.3 g weight||5 min||Differentiation ↑|
|Hu [||AoSMC (human)||1 Hz||FX-5000||16 %||Collagen I||0–30 min||Differentiation ↓|
|Butcher [||AoSMC (rat)||1 Hz||Custom||10 %||Collagen I, Fibronectin, Cel-tak||Equibiaxial||48 h||Sinusoidal||Differentiation ↓|
|Wan [||AoSMC (rat)||1.25 Hz||FX-4000||5 %, 15 %||Collagen I||24 h||Differentiation ↓|
|Rodriguez [||AoSMC (rat)||1 Hz||FX-5000||10 %||Collagen I||Uniaxial||0–24 h||Sinusoidal||Differentiation ↓|
|Song [||Venous VSMC (rat)||1 Hz||Custom||0–24 h||Differentiation ↑|
|Seo [||AoSMC (rat)||1 Hz||FX-4000||0–10 %||Pronectin||0–12 h||MMP-2 ↑|
|Yamashita [||AoSMC (rat)||0.5 Hz||STREX||2 %, 5 %, 20 %||Laminin||Uniaxial||48 h||MMP-2 ↑|
|Grote [||AoSMC (mouse)||0.5 Hz||FX-3000||15 %||Collagen I||0–24 h||MMP-2 ↑|
|Rodriguez [||AoSMC (rat)||1 Hz||FX-5000||10 %||Collagen I||Uniaxial||0–24 h||Sinusoidal||Migration ↑|
|Chiu [||AoSMC (rat)||1 Hz||FX-2000||10 %, 20 %||0–30 h||Sinusoidal||Migration ↑|
|Li [||AoSMC (mouse)||1 Hz||FX-4000||5 %, 15 %, 20 %||Collagen I||0–24 h||Migration ↑|
|Scherer [||Arterial SMC (human)||0.5 Hz||FX-5000||0–13 %||Collagen I||24 h||Migration ↑|
Since abnormal proliferation of VSMCs plays a significant role in the pathogenesis of vascular diseases such as atherosclerosis and hypertension [18–21], it follows that a clear understanding of the effect of cyclic stretch on VSMC proliferation is critical. Generally, cyclic stretch increases the rate of VSMC proliferation under
The previous data are in contrast with those observed by Guha
Stretch-induced cellular proliferation is also dependent on the effects exerted by the small non-coding molecules known as microRNAs which silence RNA by base pairing with complementary sequences within mRNA molecules . It was previously found that in rat venous VSMCs, stretch downregulated miR-223 and miR-153, stimulating proliferation via activation of insulin-like growth factor-1 receptor (IGF-1R) . Similarly, 16 % elongation of human aortic SMCs (HASMCs) resulted in enhanced miR-21 expression, which occurred via activation of the transcription factor, activator protein-1, and ultimately increased the rate of cellular proliferation . Collectively, these findings suggest that stretch-induced increases in proliferation may be, at least partially, regulated by non-coding RNAs which poses the notion that other non-coding RNAs, such as long non-coding RNAs, may also play a role in regulating VSMC response to mechanical stress.
The aforementioned studies clearly demonstrate that VSMC responses
Dysregulated apoptosis is also a key contributor to the pathogenesis of various cardiovascular diseases. Increased apoptosis has been linked to atherosclerosis, heart failure, and diabetes [38–40] and mechanical stress has been shown to upregulate VSMC apoptosis [28, 29, 32, 41–43]. Stretch exposure promoted apoptosis through the induction of p53 upregulated modulator of apoptosis in human VSMCs and β1-integrin activation of p38 MAPK in rat VSMCs [41, 42]. In porcine VSMCs, increased apoptosis occurred in parallel with activation of the p38 MAPK and c-Jun N-terminal kinase pathways following 25 % stretch . Interestingly there was no significant increase in apoptosis seen with 7 % elongation suggesting that the stretch-dependent apoptotic response may also be dependent on the degree of stretch. In HASMCs, 16 % stretch has been associated with parallel elevations in apoptosis and miR-21 expression . Studies using the Heart(P) pacemaker waveform were consistent with the general finding that stretch increased rat VSMC apoptosis [28, 29].
It is noteworthy that data has also suggested that stretch-induced apoptosis differs in VSMCs depending on their phenotype. 10 % stretch was found to induce apoptosis in differentiated, but not undifferentiated porcine VSMCs . However, it was previously demonstrated that stretch generally induces phenotypic switching from a differentiated to undifferentiated state [45–48], begging the question of whether the differentiated cells responded to the stretching stimulus. The VSMCs used in this study were also derived from veins, instead of the more commonly studied arterial SMCs, which may also have affected apoptotic response.
Characterization of the whole-heart and aortic smooth muscle cell apoptosis in SHR showed increases in apoptosis
It is of particular interest that both proliferation and apoptosis seem to be generally upregulated as a result of stretch in VSMC cultures. This may suggest that there is a compensatory mechanism in place to counteract the increase or decrease in cell survival. Future studies aimed at elucidating the mechanisms by which pro- and anti-survival factors interact during conditions of mechanical stress are warranted.
VSMCs are plastic cells, altering their phenotype based on the surrounding microenvironment [3, 5]. Studies have shown that VSMCs undergo phenotypic switching in response to cyclic mechanical stress [17, 26, 45–48, 51]. RASMCs that had been subjected to 10 % elongation underwent phenotypic switching from the contractile to the synthetic phenotype, characterized by a decrease in alpha smooth muscle actin and calponin . It was also observed that 16 % stretch inhibited miR-145, a positive regulator of the HASMC differentiation stimulator, myocardin, via activation of the ERK pathway . Wan
The above mentioned
The discrepancies in the phenotypic switching data available to date may not be easily resolved solely by stratifying results based on axis of stretch. Yao
As VSMCs adopt their synthetic phenotype, the rates of proliferation and migration increase [3–5]. During atherogenesis and tissue repair after vascular injury, VSMCs migrate from the tunica media to the tunica intima . Since VSMC migration is correlated with the pathogenesis of vascular diseases, studies have been conducted to determine the effects of mechanical stress on migration
VSMCs in the vessel wall are arranged in the form of a fibrous helix. In response to mechanical stimuli during development, angiogenesis, and vascular remodeling, VSMCs undergo changes in alignment . The application of 20 and 10 % uniaxial cyclic stretch induced aortic SMC alignment perpendicular to the axis of stretch via activation of the p38 MAPK pathway and the induction of NO synthesis, respectively [59, 60]. Equibiaxial cyclic stretch has also been shown to induce VSMC alignment
To study VSMC alignment
Vascular remodeling generally occurs as a response to hemodynamic changes in the blood vessel and is often a critical pathophysiological component of many cardiovascular diseases. It involves changes in proliferation, apoptosis, migration, and reorganization of the ECM . Matrix metalloproteinases (MMPs) have been implicated in the decomposition of the ECM and are largely involved in vascular remodeling . Researchers have established that, under conditions of mechanical stress, cultured VSMCs from rat and mouse experienced increases in the expression and activity of MMP-2, which was modulated by the Akt pathway, periostin/focal adhesion kinase (FAK) system and ROS production [67–69].
Increased expression and activity of MMPs in response to stretch have been observed in VSMCs from the aortas of SHR. These cells were found to have higher MMP-9 levels and activity relative to those from aortas of normotensive controls . Similarly, left ventricular tissue from these rats had higher levels of both MMP-2 and MMP-9 activity . Human saphenous vein grafts subjected to uniaxial stretch to a maximum elongation of 150 % of their resting length for 5 s demonstrated enhanced pro-MMP-9 expression and MMP-2 activity 3–5 days after later . In contrast, Lin
In order to more accurately assess
The extensive diversity of the data obtained from VSMCs exposed to mechanical stress indicates that there are many variables that can influence stretch-induced responses. The frequency, duration, degree and axis of stretch, along with the plate substrate, origin of VSMC (vein or artery) may affect downstream responses of stretched cells. In addition, factors such as cell passage number, content of culture media, and calibration of equipment, may also contribute the discrepancies reported for VSMC stretch response. Accordingly, while the available models may provide important information, it is crucial to identify and simultaneously measure key biomarkers that can confirm VSMC stretch-mediated responses. These biomarkers are paramount to elucidating how variations of stretch conditions influence stretch-induced VSMC responses.
This work was supported by in part by a grant from the Heart and Stroke Foundation of Canada to SV. LEM is the recipient of a graduate fellowship from the University of Toronto Department of Pharmacology & Toxicology.
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