YAP/TAZ as mechanobiological signaling pathway in cardiovascular physiological regulation and pathogenesis.

Cardiovascular diseases (CVDs) persistently rank as a leading cause of premature death and illness worldwide. The Hippo signaling pathway, known for its highly conserved nature and integral role in regulating organ size, tissue homeostasis, and stem cell function, has been identified as a critical factor in the pathogenesis of CVDs. Recent findings underscore the significance of the Yes-associated protein (YAP) and the Transcriptional Coactivator with PDZ-binding motif (TAZ), collectively referred to as YAP/TAZ.

Potential Benefits and Risks Associated with the Use of Statins.

HMG-CoA reductase inhibitors, commonly known as statins, are the primary treatment choice for cardiovascular diseases, which stand as the leading global cause of mortality. Statins also offer various pleiotropic effects, including improved endothelial function, anti-inflammatory properties, reduced oxidative stress, anti-thrombotic effects, and the stabilization of atherosclerotic plaques. However, the usage of statins can be accompanied by a range of adverse effects, such as the development of type 2 diabetes mellitus, muscular symptoms, liver toxicity, kidney diseases, cataracts, hemorrhagic strokes, and psychiatric complications.

Exploring the difference in the mechanics of vascular smooth muscle cells from wild-type and apolipoprotein-E knockout mice.

Atherosclerosis-related cardiovascular diseases are a leading cause of mortality worldwide. Vascular smooth muscle cells (VSMCs) comprise the medial layer of the arterial wall and undergo phenotypic switching during atherosclerosis to a synthetic phenotype capable of proliferation and migration. The surrounding environment undergoes alterations in extracellular matrix (ECM) stiffness and composition and an increase in cholesterol content.

On-Site Differentiation of Human Mesenchymal Stem Cells into Vascular Cells on Extracellular Matrix Scaffold Under Mechanical Stimulations for Vascular Tissue Engineering.

Small-diameter vascular grafts are considered to be a promising strategy to treat late-stage vascular diseases, one of the largest causes of morbidity and mortality worldwide. However, limited sources of functional vascular cells remain a major obstacle in vascular tissue engineering. Here we describe a novel approach whereby functional vascular cells were obtained by on-site differentiation of human mesenchymal stem cells on a vascular extracellular matrix scaffold under mechanical stimulations in a rotary bioreactor, which has the potential to work as an alternative source for robust implantable artificial vessel grafts.

Electrospun nanofiber scaffold for vascular tissue engineering.

Due to the prevalence of cardiovascular diseases, there is a large need for small diameter vascular grafts that cannot be fulfilled using autologous vessels. Although medium to large diameter synthetic vessels are in use, no suitable small diameter vascular graft has been developed due to the unique dynamic environment that exists in small vessels. To achieve long term patency, a successful tissue engineered vascular graft would need to closely match the mechanical properties of native tissue, be non-thrombotic and non-immunogenic, and elicit the proper healing response and undergo remodeling to incorporate into the native vasculature.

An Elastic Mineralized 3D Electrospun PCL Nanofibrous Scaffold for Drug Release and Bone Tissue Engineering.

Complex shaped and critical-sized bone defects have been a clinical challenge for many years. Scaffold-based strategies such as hydrogels provide localized drug release while filling complex defect shapes, but ultimately possess weaknesses in low mechanical strength alongside a lack of macroporous and collagen-mimicking nanofibrous structures. Thus, there is a demand for mechanically strong, extracellular matrix (ECM) mimicking scaffolds that can robustly fit complex shaped critical sized defects and simultaneously provide localized, sustained, multiple growth factor release.

Low doses of zeolitic imidazolate framework-8 nanoparticles alter the actin organization and contractility of vascular smooth muscle cells.

Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles have emerged as a promising platform for drug delivery and controlled release. Considering most ZIF-8 nanoparticle drug carriers are designed to be administered intravenously, and thus would directly contact vascular smooth muscle cells (VSMCs) in many circumstances, the potential interactions of ZIF-8 nanoparticles with VSMCs require investigation. Here, the effects of low doses of ZIF-8 nanoparticles on VSMC morphology, actin organization, and contractility are investigated.

Gelatin-crosslinked pectin nanofiber mats allowing cell infiltration.

Pectin nanofiber mats are promising tissue engineering scaffolds but suffer from poor cell infiltration. In this study, gelatin, a collagen derived cell adhesive protein, was used to crosslink the electrospun nanofibers of periodate oxidized pectin. Cell culture experiment results demonstrated that cells were able to grow into the gelatin-crosslinked pectin nanofiber mats rather than only spread on mat surface.

Extracellular Matrix Proteins and Substrate Stiffness Synergistically Regulate Vascular Smooth Muscle Cell Migration and Cortical Cytoskeleton Organization.

Vascular smooth muscle cell (VSMC) migration is a critical step in the progression of cardiovascular disease and aging. Migrating VSMCs encounter a highly heterogeneous environment with the varying extracellular matrix (ECM) composition due to the differential synthesis of collagen and fibronectin (FN) in different regions and greatly changing stiffness, ranging from the soft necrotic core of plaques to hard calcifications within blood vessel walls. In this study, we demonstrate an application of a two-dimensional (2D) model consisting of an elastically tunable polyacrylamide gel of varying stiffness and ECM protein coating to study VSMC migration.

Vessel graft fabricated by the on-site differentiation of human mesenchymal stem cells towards vascular cells on vascular extracellular matrix scaffold under mechanical stimulation in a rotary bioreactor.

Although a significant number of studies on vascular tissue engineering have been reported, the current availability of vessel substitutes in the clinic remains limited mainly due to the mismatch of their mechanical properties and biological functions with native vessels. In this study, a novel approach to fabricating a vessel graft for vascular tissue engineering was developed by promoting differentiation of human bone marrow mesenchymal stem cells (MSCs) into endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) on a native vascular extracellular matrix (ECM) scaffold in a rotary bioreactor. The expression levels of CD31 and vWF, and the LDL uptake capacity as well as the angiogenesis capability of the EC-like cells in the dynamic culture system were significantly enhanced compared to the static system.

Statin-mediated cholesterol depletion exerts coordinated effects on the alterations in rat vascular smooth muscle cell biomechanics and migration.

Key Points: This study demonstrates and evaluates the changes in rat vascular smooth muscle cell biomechanics following statin-mediated cholesterol depletion. Evidence is presented to show correlated changes in migration and adhesion of vascular smooth muscle cells to extracellular matrix proteins fibronectin and collagen. Concurrently, integrin α5 expression was enhanced but not integrin α2.

The interplay of membrane cholesterol and substrate on vascular smooth muscle biomechanics.

Cardiovascular disease (CVD) remains the primary cause of death worldwide. Specifically, atherosclerosis is a CVD characterized as a slow progressing chronic inflammatory disease. During atherosclerosis, vascular walls accumulate cholesterol and cause fatty streak formation.

Fabrication and Characterization of Pectin Hydrogel Nanofiber Scaffolds for Differentiation of Mesenchymal Stem Cells into Vascular Cells.

Despite significant progress over the past few decades, creating a tissue-engineered vascular graft with replicated functions of native blood vessels remains a challenge due to the mismatch in mechanical properties, low biological function, and rapid occlusion caused by restenosis of small diameter vessel grafts (<6 mm diameter). A scaffold with similar mechanical properties and biocompatibility to the host tissue is ideally needed for the attachment and proliferation of cells to support the building of engineered tissue. In this study, pectin hydrogel nanofiber scaffolds with two different oxidation degrees (25 and 50%) were prepared by a multistep methodology including periodate oxidation, electrospinning, and adipic acid dihydrazide crosslinking.

Membrane cholesterol and substrate stiffness co-ordinate to induce the remodelling of the cytoskeleton and the alteration in the biomechanics of vascular smooth muscle cells.

Aims: Cholesterol not only deposits in foam cells at the atherosclerotic plaque, but also plays an important role as a regulator of cell migration in atherogenesis. In addition, the progression of atherosclerosis leads to arterial wall stiffening, and thus altering the micromechanical environment of vascular smooth muscle cells (VSMCs) in vivo. Our studies aim to test the hypothesis that membrane cholesterol and substrate stiffness co-ordinate to regulate VSMCs biomechanics, and thus potentially regulate VSMCs migration and atherosclerotic plaque formation.

Vascular extracellular matrix and fibroblasts-coculture directed differentiation of human mesenchymal stem cells toward smooth muscle-like cells for vascular tissue engineering.

Construction of an artificial vascular graft is widely considered a promising strategy in vascular tissue engineering. However, limited sources of functional vascular smooth muscle cells (VSMCs) remain a major obstacle in vascular tissue engineering. In this study, we innovatively developed an approach to obtain functional VSMCs by onsite differentiating human bone marrow-derived mesenchymal stem cells (MSCs) directed by decellularized extracellular matrix (ECM) and fibroblasts.

Temporal and molecular dynamics of human metastatic breast carcinoma cell adhesive interactions with human bone marrow endothelium analyzed by single-cell force spectroscopy.

Bone is a common site of metastasis for breast cancer and the mechanisms of metastasis are not fully elucidated. The purpose of our study was to characterize temporal and molecular dynamics of adhesive interactions between human breast cancer cells (HBCC) and human bone marrow endothelium (HBME) with piconewton resolution using atomic force microscopy (AFM). In adhesion experiments, a single breast cancer cell, MDA-MB-231 (MB231) or MDA-MB-435 (MB435) was attached to the AFM cantilever and brought into contact with a confluent HBME monolayer for different time periods (0.

Tailoring weight ratio of PCL/PLA in electrospun three-dimensional nanofibrous scaffolds and the effect on osteogenic differentiation of stem cells.

Three-dimensional (3D) scaffolds as artificial ECMs have been extensively studied to mimic the critical features of natural ECMs. To develop more clinically relevant 3D scaffolds, electrospun nanofibrous scaffolds with different weight ratios of PCL/PLA (i.e.

Functionalization of PCL-3D Electrospun Nanofibrous Scaffolds for Improved BMP2-Induced Bone Formation.

Bone morphogenic protein 2 (BMP2) is a key growth factor for bone regeneration, possessing FDA approval for orthopedic applications. BMP2 is often required in supratherapeutic doses clinically, yielding adverse side effects and substantial treatment costs. Considering the crucial role of materials for BMPs delivery and cell osteogenic differentiation, we devote to engineering an innovative bone-matrix mimicking niche to improve low dose of BMP2-induced bone formation.

Spontaneous oscillation in cell adhesion and stiffness measured using atomic force microscopy.

Atomic force microscopy (AFM) is an attractive technique for studying biomechanical and morphological changes in live cells. Using real-time AFM monitoring of cellular mechanical properties, spontaneous oscillations in cell stiffness and cell adhesion to the extracellular matrix (ECM) have been found. However, the lack of automated analytical approaches to systematically extract oscillatory signals, and noise filtering from a large set of AFM data, is a significant obstacle when quantifying and interpreting the dynamic characteristics of live cells.

Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles.

Key Points: Candesartan, an inverse agonist of the type 1 angiotensin II receptor (AT R), causes a concentration-dependent inhibition of pressure-dependent myogenic tone consistent with previous reports of mechanosensitivity of this G protein-coupled receptor. Mechanoactivation of the AT R occurs independently of local angiotensin II production and the type 2 angiotensin receptor. Mechanoactivation of the AT R stimulates actin polymerization by a protein kinase C-dependent mechanism, but independently of a change in intracellular Ca .

Vascular smooth muscle cell stiffness and adhesion to collagen I modified by vasoactive agonists.

In vascular smooth muscle cells (VSMCs) integrin-mediated adhesion to extracellular matrix (ECM) proteins play important roles in sustaining vascular tone and resistance. The main goal of this study was to determine whether VSMCs adhesion to type I collagen (COL-I) was altered in parallel with the changes in the VSMCs contractile state induced by vasoconstrictors and vasodilators. VSMCs were isolated from rat cremaster skeletal muscle arterioles and maintained in primary culture without passage.

Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging.

Hypertension and aging are both recognized to increase aortic stiffness, but their interactions are not completely understood. Most previous studies have attributed increased aortic stiffness to changes in extracellular matrix proteins that alter the mechanical properties of the vascular wall. Alternatively, we hypothesized that a significant component of increased vascular stiffness in hypertension is due to changes in the mechanical and adhesive properties of vascular smooth muscle cells, and that aging would augment the contribution from vascular smooth muscle cells when compared with the extracellular matrix.

Lysophosphatidic acid induces integrin activation in vascular smooth muscle and alters arteriolar myogenic vasoconstriction.

In vascular smooth muscle cells (VSMC) increased integrin adhesion to extracellular matrix (ECM) proteins, as well as the production of reactive oxygen species (ROS) are strongly stimulated by lysophosphatidic acid (LPA). We hypothesized that LPA-induced generation of ROS increases integrin adhesion to the ECM. Using atomic force microscopy (AFM) we determined the effects of LPA on integrin adhesion to fibronectin (FN) in VSMC isolated from rat (Sprague-Dawley) skeletal muscle arterioles.