Mechanical behavior and wall remodeling of blood vessels under axial twist / 医用生物力学

Blood vessels are often subjected to axial torsion (or twist) due to body movement or surgery. However, there are few studies on blood vessel under twist. This review first summarizes the clinical observation on the twist of blood vessels and then presents what we know about the mechanical behaviors of blood vessel under twist, including the constitutive models. The state of art researches on the remodeling of blood vessels under twist via ex vivo organ culture, in vivo animal experiments, and mathematical model simulations are further discussed. It is our hope that this review will draw attention for further in-depth studies on the behavior and remodeling of blood vessels under twist.

Review and prospect of Journal of Medical Biomechanics on the 30th Anniversary / 医用生物力学

Journal of Medical Biomechanics was founded in 1986. As a technical periodical, the journal aims at reflecting the latest scientific and clinical achievement and progress in the field of biomechanics, and promoting academic exchange of biomechanics both in China and abroad. By June 2016, the journal has officially published a total of 31 volumes and 124 issues, and great progress has been achieved in its publishing quality and academic influence. In this article, the 30-year development of the journal is reviewed, and future work is prospected in the aspect of improving quality, digitalization and internationalization of the journal.

Regulating effect of microRNA-21 on the expression of extracellular matrix of vascular smooth muscle cells under vascular remodeling of hypertension / 医用生物力学

Objective To investigate the regulating effect and mechanism of microRNA-21 (miR-21) on extracellular matrix (ECM) of vascular smooth muscle cells (VSMCs) by vascular remodeling of hypertension. Methods By narrowing the abdominal aorta in rats, the hypertension models were established and divided into 2-week hypertension group and 4-week hypertension group, and sham-operated group was also established as control. VSMCs from the rat aorta were subjected to 0% (static), 5% (normal) and 15%（hypertensive）elongation strain at a constant frequency of 1.25 Hz and duration of 12 hours, respectively. The expressions of Smad 7 and ECM were detected by Western blotting, and the expression of miR-21 was examined by Real-time RT-PCR. Finally, miR-21 siRNA was used to study the role of miR-21 in the mechanical strain-induced expression of ECM, miR-21 and Smad 7. Results Compared with the sham-operated group, ECM and miR-21 in thoracic aorta of 2-week hypertension group were significantly elevated. Collagen I, collagen III and miR-21 in thoracic aorta of 4-week hypertension group were significantly elevated. Compared with the static and 5% strain groups, the protein expression of collagen I in VSMCs did not show significant change, but the protein expression of collagen III was significantly elevated and Smad 7 expression was significantly decreased in 15% strain group. The cyclic strain also enhanced miR-21 expression in VSMCs. miR-21 inhibitor effectively decreased the expression of miR-21 in VSMCs and protein level of collagen III, while enhanced Smad 7 expression under the static and 15% strain. Conclusions The vascular remodeling of hypertension causes the high expressions of ECM and miR-21. The cyclic strain induces the high expression of miR-21, which via Smad 7 results in enhancing the expression of ECM, collagen III especially, in VSMCs under vascular remodeling of hypertension.

The role of microRNA-34a in low shear stress- induced proliferation of vascular smooth muscle cells / 医用生物力学

Objective To investigate the role of microRNA-34a (miR-34a) in the proliferation of vascular smooth muscle cells (VSMCs) induced by low shear stress (LowSS). Methods Using co-culture parallel plate flow chamber system, endothelial cells (ECs) and VSMCs were co-cultured and applied with normal shear stress (1.5 Pa) and LowSS (0.5 Pa) for 12 h. The expression of proliferating cell nuclear antigen (PCNA) in the co-cultured VSMCs was detected by Western blotting to determine the proliferation capacity of VSMCs. Real-time PCR was used to examine the miR levels of miR-34a in the co-cultured VSMCs. The target proteins of miR-34a were predicted by TargetScan, miRWalk and some other websites. Western blotting was used to detect expression of Forkhead box j2 (Foxj2) in the co-cultured VSMCs. Mimics and inhibitor were used to up-regulate or inhibit the expression of miR-34a, and then the expression of Foxj2 and PCNA was detected by Western blotting to verify the regulation relationship between miR 34a and Foxj2. Results Compared with NSS, LowSS promoted the PCNA expression and significantly up-regulated the miR-34a expression in the co-cultured VSMCs. Foxj2 was predicted to be the downstream target protein of miR-34a by TargetScan, miRWalk and some other websites. Foxj2 expression decreased significantly in the co-cultured VSMCs under LowSS application. Under static condition, the expression of Foxj2 obviously decreased and the expression of PCNA obviously increased by up-regulating miR-34a expression in VSMCs. While inhibiting the expression of miR-34a in VSMCs would result in a significant increase in the expression of Foxj2 and a significant decrease in the expression of PCNA. Conclusions LowSS can promote the proliferation of VSMCs by regulating miR-34a and target protein Foxj2 in the co-cultured VSMCs. This research finding will provide new mechanobiological experimental reference for further illustrating the pathogenesis of atherosclerosis and finding the therapeutic targets for drugs.

TNF-α promotes the quantity and ICAM-1 expression of endothelial microparticles / 医用生物力学

Objective To study the role of cyclic strain-modulated tumor necrosis factor-α (TNF-α) played in the quantity and intercellular cell adhesion molecule-1(ICAM-1) expression of endothelial microparticles (EMPs). Methods The endothelial cells (ECs) primarily cultured from rat aorta were applied with 5% cyclic strain (to simulate normal physiological condition) and 18% cyclic strain (to simulate hyper-tension condition), respectively, by using FX-4000T cyclic stain loading system for 24 hours at the loading frequency of 1.25 Hz. The mRNA expression of TNF-α under different amplitudes of cyclic strain was determined by real time-PCR. The TNF-α was then used to stimulate the ECs from rat aorta, and the supernatants were collected and ultracentrifuged to get endothelial microparticles (EMPs), which were then identified by lipophilic styryl membrane staining and transmission electron microscope for morphological identification. The quantities of Annexin V positive EMPs under TNF-α stimulation were counted by flow cytometer and ICAM-1 expression on EMPs was detected as well. Results Compared with the 5% normal cyclic strain, under 18% high cyclic strain condition,the mRNA expression of TNF-α in ECs increased significantly. TNF-α could then significantly up-regulate the production of Annexin V positive EMPs and promote the expression of ICAM-1 on EMPs. Conclusions The over-expression of TNF-α in ECs under high cyclic strain might mediate the high production of EMPs and over-expression of ICAM-1 on EMPs. The research findings will provide new experiment evidence for further studying the role of EPCs in the mechanobiological mechanism of vascular remodeling.

Shear stress modulates the proliferation of vascular smooth muscle cells via receptor for activated C kinase 1 / 医用生物力学

Objective To investigate the role of receptor for activated C kinase 1 (RACK1) in vascular smooth muscle cells (VSMCs) proliferation modulated by co-cultured endothelial cells (ECs) and shear stress. Methods Using EC/VSMC co-cultured parallel plate flow chamber system, two levels of shear stress, i.e. low shear stress (LowSS, 0.5 Pa) and normal shear stress (NSS, 1.5 Pa), were applied for 12 h. BrdU ELISA was used to detect the proliferation of VSMCs, and Western blot was used to detect the protein expressions of RACK1 and phosphor-Akt. Under the static condition, RNA interference was used to suppress the expression of RACK1 in VSMCs, and then the proliferation of VSMCs and expressions of RACK1 and phosphor-Akt were detected. By using co-culture model (ECs/VSMCs) and separated culture model (ECs//VSMCs), the effect of ECs on expressions of RACK1 and phosphor-Akt in VSMCs was further analyzed. Results Comparative proteomic analysis revealed that LowSS increased the expression of RACK1 in rat aorta. In vitro experiments showed that LowSS induced the proliferation, expressions of RACK1 and phospho Akt in VSMCs co-cultured with ECs. Target RNA interference of RACK1 significantly decreased the proliferation of VSMCs, and the phosphorylation of Akt. In comparison with ECs//VSMCs (separated culture) group, the expression of RACK1 and phosphor-Akt were both up-regulated in the VSMCs co-cultured with ECs (ECs/VSMCs group). Conclusions The expression of RACK1 in VSMCs was modulated by shear stress and neighboring ECs, which might induce cellular proliferation via PI3K/Akt pathway. The investigation on VSMC proliferation and the involved biomechanical mechanism will contribute to understanding and help preventing the pathogenesis and progress of atherosclerosis.

The role of Rab28 and ERK in low shear stress induced migration of vascular smooth muscle cells / 医用生物力学

Objective To study the role of abnormally changed migration of vascular smooth muscle cells (VSMCs) induced by low shear stress (LowSS) in vascular remodeling during atherosclerosis as well as the molecular mechanism involved in this process. Methods By using comparative proteomic analysis with two-dimensional electrophoresis combined with mass spectrometry, differential protein expression profiles of cultured vascular tissues under normal shear stress (NSS) (1.5 Pa) and LowSS (0.5 Pa) were studied. Using endothelial cells (ECs) and VSMCs co-cultured parallel plate flow chamber system, two levels of shear stress i.e. LowSS and NSS, were applied, respectively. Western blot was used to detect the protein expressions of Rab28 and phosphor-ERK. Transwell system was used to detect the migration ability of VSMCs. After using RNA interference and ERK inhibitor PD98059 to decrease the expressions of Rab28 and phosphor-ERK, respectively, the migration ability of VSMCs was observed again. Results The expression of Rab28 in the cultured rat aorta was significantly up-regulated by the LowSS (0.5 Pa) application in comparison with the NSS (1.5 Pa). The migration, expressions of Rab28, and phosphorylation of ERK in VSMCs were significantly increased by the LowSS application. Target RNA interference of Rab28 significantly decreased the migration of VSMCs, but had no specific effect on the phosphorylation of ERK. Target inhibitor of ERK, PD98059, significantly decreased both the migration and Rab28 expression in VSMCs. Conclusions The LowSS may increase the phosphorylation of ERK and then increase the expression of Rab28 in VSMCs, which subsequently modulate VSMC migration during vascular remodeling. The investigation on the role of Rab28 and its signal path in LowSS-regulated VSMCs as well as the molecular mechanism might provide a biomechanical reference for understanding the pathogenesis of vascular remodeling during atherosclerosis and finding the therapeutic target of new drugs.

The role of FOXO1 in cyclic stretch induced-proliferation of vascular smooth muscle cells during hypertension / 医用生物力学

Objective To investigate the role of pathologically increased-cyclic stretch in proliferation of vascular smooth muscle cells (VSMCs) during hypertension, and the effect of Forkhead box protein O1 (FOXO1) during this process. Methods Coarctation of abdominal aorta above kidney artery of rat was used as hypertensive animal model, and sham-operated animal as control. FX-4000 cyclic stretch loading system was used to apply 5% physiologically cyclic stretch and 15% pathologically cyclic stretch during hypertension on VSMCs in vitro. Western blot was used to reveal the expressions of FOXO1 and phosphor-FOXO1 in VSMCs, and BrdU kit to detect the proliferation of VSMCs in vitro. By using RNA interference in static, the role of FOXO1 on cell proliferation was further detected. Results After abdominal aorta coarctation for 2 and 4 weeks, respectively, the blood pressure was significantly increased compared with the sham operated rats. The proliferation of vascular cells in aorta of hypertensive rat was significantly increased, and so did the expressions of FOXO1 and phosphor-FOXO1. In vitro experiment revealed that 15% cyclic stretch remarkably increased the proliferation and expressions of FOXO1 and phospho FOXO1 in VSMCs. Target siRNA transfection in static decreased the expression of FOXO1 and phosphor-FOXO1, as well as the proliferation of VSMCs. Conclusions Pathologically increased-cyclic stretch may increase the expression and phosphorylation of FOXO1, subsequently modulate VSMC proliferation during hypertension. Based on animal models, this study intends to reveal the role of FOXO1 in vascular reconstruction of hypertension and the involved biomechanical mechanism, so as to make the mechanobiological mechanism of hypertension explicit and discover new target in the prevention and treatment of vascular remodeling.

Two methods of constructing the residual stress on vessel and its application / 医用生物力学

Objective To study distributions of the residual stresses on blood vessel, and to provide the biomechanical basis for the finite element research on stress changes in blood vessel. Methods The semi-inverse method was used for getting distributions of residual stresses on blood vessel and the result was compared with that from Commercial Software ABAQUS. On that basis, the interaction between the vessel and implanted stent was simulated to get the influence of residual stress on blood vessel. Results Distributions of three normal stresses on blood vessel obtained from the two methods were almost consistent. It is the residual stress that led to the change of vessel stress distributions, and the position of maximal stress was transformed from the inside to the outside of the vessel. Conclusions Assuming that the vessel has homogeneity and isotropic, both the semi-inverse method and the finite element method would get the similar residual stress distributions; significant differences existed between the stress states of vessel with or without considering residual stress. The stress at the inside of vessel was reduced obviously. Consideration of residual stress will be helpful for understanding the real stress state of vessel after stent deployment and providing references for the optimization design of stent.

Vascular remodeling under axial tension / 医用生物力学

Arteries in vivo are subjected to lumen pressure, shear flow and axial tension due to surrounding tissue tethering. The axial stress affects arterial function including its response to pressure and flow. While the effects of blood pressure and shear flow are well documented, the effects of axial tension on vascular remodeling have just gradually gained attention recently. This review summarizes the results on the observation of the axial tension in arteries and responses of arteries to elevation and reduction of the axial stress. It is concluded that the axial tension in arteries plays an important role in regulating normal arterial function and tissue remodeling and adaptation and disease development. Research on vascular remodeling under axial tension shall strengthen the understanding of normal physiological functions and pathological changes of the arteries.

Effect from different pore sizes of co-culture inserts on the permeability of platelet derived growth factor / 医用生物力学

Objective To investigate the effect from different pore sizes of co culture inserts on the permeability of biomacromolecules through polyethylene terephthalate (PET) membrane so as to solve the key technology problem in mechanobiology experiment on vascular cells. Methods Inserts with 0.4 μm and 1.0 μm pores on the PET membrane were studied using flow chamber system. Low shear stress was subjected to the co-cultured system of endothelial cell (EC)/vascular smooth muscle cell (VSMC) and the concentration of platelet-derived growth factor BB (PDGF-BB) was detected by ELISA. Under the static condition, vascular cells were cultured on the plate (with no cell on PET membrane), on the outer side of PET membrane, and on the both sides of PET membrane, respectively. Then the recombinants PDGF-BB (rPDGF-BB) were added on the different sides of PET membrane. Western blotting was used to detect the change in expressions of p-ERK1/2, p-Akt and Lamin after cells were stimulated by rPGDF BB. Results After low shear stress subjection for 12 h, the concentration of PDGF-BB in the medium from VSMC side was significantly higher than that from EC-side. rPDGF-BB passed through 0.4 μm and 1.0 μm pores on the PET membrane and modulated expressions of p-ERK1/2, p-Akt and Lamin A in cells cultured on the opposite side of PET membrane and cells cultured on the plate separately. When cells were cultured on the both sides of PET membrane, rPDGF-BB only stimulated cells cultured on the same side of 0.4 μm pores on PET membrane, but had no specific effect on cells cultured on the opposite side. Conclusions PET membrane with both 0.4 μm and 1.0 μm pores was permeable to PDGF-BB, and cells cultured on the membrane could affect the permeability. The efficiency of PDGF BB passing through 0.4 μm pores was significantly repressed with cells cultured on the both sides, which was more similar to that in vivo.

Effects of hypertension and low shear stress on common carotid remodeling in rats / 医用生物力学

Objective To study the mechanisms of vascular remodeling induced by hypertension and/or low shear stress, which will be helpful in the prevention, diagnosis and treatment of cardiovascular diseases. Method The models of low shear stress in carotid artery or of hypertension were established by the ligation of partial distal branches of the left common carotid artery (LCA) or by the coarctation of aorta in SD rats, respectively. For some rats, the low shear stress in LCA was accompanied by the hypertension. The wall thickness and the ratio of wall thickness to inner diameter were determined by morphometrical approach. The MMP-2 activity was detected by gel zymography, and the expression of proteins, including p-Akt, Rho GDIα, was verified by Western blotting in LCA. Results When LCA was subjected to hypertension or low shear stress, MMP-2 activity, the wall thickness, and the ratio of wall thickness to inner diameter were all increased significantly. They were further enhanced when the hypertension and low shear stress were both existed, which would speed the vascular remodeling. Low shear stress induced the expression of p Akt, and the lower shear stress, the higher p-Akt expression would be. However, the highest expression of p-Akt was observed in LCA of hypertension accompanied by low shear stress. The expression of Rho GDIα was upregulated in LCA by either low shear stress or hypertension. The highest expression of Rho GDIα was observed in LCA of hypertension accompanied by low shear stress. Conclusions Vascular remodeling could be mostly influenced in LCA subjected to low shear stress accompanied by hypertension, which was also regulated through the changing expression of p-Akt and Rho GDIα.

Recent advances in cardiovascular biomechanics / 医用生物力学

There are two important recent advances in cardiovascular biomechanics. One is cardiovascular mechanobiology, which illustrates how mechanical factors can generate biological effects resulting in vascular remodeling. By studying signal transduction pathway in the cardiovascular system and means of mechanical control, cardiovascular mechanobiology aims to investigate the nature of cardiovascular disease at cellular and molecular level. The other is cardiovascular numerical simulation and individual design of surgery operation on the basis of clinical images. Based on fluid mechanics, clinical images as well as advanced measuring and testing methods of flow field, cardiovascular numerical simulation and quantitative analysis can be conducted. New in vivo techniques for studying cardiovascular function and the design of individual surgery system can provide biomechanical solutions for the diagnosis, therapy and prewarning of cardiovascular disease. In this special issue, seven papers on cardiovascular biomechanics are published, covering vascular cell mechanobiology and cardiovascular numerical simulation connected with the clinical problems tightly. These papers show us some recent advances in cardiovascular biomechanics in China.

Shear stress and vascular smooth muscle cells modulate the proliferation of endothelial cells via TGFβ1 and p-Akt pathways / 医用生物力学

Objective To investigate the effects of shear stress and vascular smooth muscle cells (VSMCs) on the proliferation of endothelial cells (ECs) and the molecular mechanism involved in. Method Using parallel-plate flow chamber system, normal shear stress of 15 dyn/cm2(1 dyn=10-5 N) was applied to ECs cultured singly and co cultured with VSMCs respectively. Then, the expression of PCNA, a molecule representing cell proliferation ability, and phosphorylation of Akt were analyzed by Western blotting in order to investigate the roles of shear stress and VSMCs in EC proliferation. Under the static condition, the expressions of PCNA and p-Akt were analyzed in ECs co-cultured with VSMCs with and without physical contact. And then TGFβ1 neutralizing antibody was employed to demonstrate the contribution of TGFβ1 in VSMCs induced EC proliferation. Results Normal shear stress decreased EC proliferation and Akt phosphorylation. VSMCs increased EC proliferation and Akt phosphorylation in both co-culture conditions with and without physical contact. Normal shear stress partly reversed the increase of proliferation and Akt phosphorylation in ECs with physical contact to VSMCs, and TGFβ1 neutralizing antibody exerted the similar effects in ECs without physical contact to VSMCs. Conclusions Normal shear stress is a protective factor with its inhibitory effect on EC proliferation. VSMCs induced EC proliferation via TGFβ1 and p Akt pathways by paracrine model.

Effect of flow shear stress gradient on the arrangement and shape of endothelial cells / 医用生物力学

Objective The effect of different flow shear stress gradient on the changes of arrangement and shape of endothelial cells was evaluated in order to investigate the effect of shear stress gradient on ECs morphology and function. Method A flow chamber system with gradient shear stress was established, in which the range of shear stress is from 15 dyn/cm2 to 6.6 dyn/cm2(1 dyn=10-5 N), and the shear stress gradient is 1.5 dyn/cm2 and 3 dyn/cm2 respectively. After ECs were subjected to the gradient shear stress for 6 hours, cell angle, cell width length ratio, as well as cell shape index of ECs under the different shear stress gradient were examined. Results The cell angles of ECs were straggling under both 1.5 dyn/cm2 and 3 dyn/cm2 shear stress gradient. The cell width length ratio and cell shape index of ECs were decreased under 1.5 dyn/cm2 shear stress gradient compared with that of 3 dyn/cm2 shear stress gradient. Conclusions The ECs show random orientation under the different shear stress gradient. The ECs are trending to stretch and elongate shape under smaller shear stress gradient, and to approach cycloid under larger shear stress gradient.

Effects of CNTF on the nuclear translocation of PKC following NMDA administration in primary hippocampal neurons / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of ciliary neurotrophic factor (CNTF) on the nuclear translocation of protein kinase C (PKC) following NMDA administration in the primary cultured hippocampal neurons.</p><p><b>METHODS</b>(1) PKCGAMMA or PKCepsilon- immunocytochemistry staining method was used after treating neurons with NMDA or CNTF. (2) The gray of the nucleus of the PKC-positive neurons were measured under the image pattern analysis system.</p><p><b>RESULTS</b>(1) After NMDA administration of different concentration and time, Nucleus appear PKCgamma and PKCepsilon activities, especially the 100 micromol/L NMDA 30 min group. (2) The gray of nucleus in CNTF + 500 micromol/L NMDA group is similar to control group.</p><p><b>CONCLUSION</b>NMDA can induce nuclear translocation of PKC in the primary cultured hippocampal neurons, and CNTF can inhibit the translocation. It suggests that the inhibition of PKC translocation induced by NMDA is one of the important reasons for the neuro-protective effects of CNTF.</p>