Proangiogenic Effect of Affinin and an Ethanolic Extract from Heliopsis longipes Roots: Ex Vivo and In Vivo Evidence

Angiogenesis, the formation of new blood vessels, underlies tissue development and repair. Some medicinal plant-derived compounds can modulate the angiogenic response. Heliopsis longipes, a Mexican medicinal plant, is widely used because of its effects on pain and inflammation. The main bioactive phytochemicals from H. longipes roots are alkamides, where affinin is the most abundant. Scientific studies show various medical effects of organic extracts of H. longipes roots and affinin that share some molecular pathways with the angiogenesis process, with the vasodilation mechanism of action being the most recent. This study investigates whether pure affinin and the ethanolic extract from Heliopsis longipes roots (HLEE) promote angiogenesis. Using the aortic ring rat assay (ex vivo method) and the direct in vivo angiogenesis assay, where angioreactors were implanted in CD1 female mice, showed that affinin and the HLEE increased vascular growth in a dose-dependent manner in both bioassays. This is the first study showing the proangiogenic effect of H. longipes. Further studies should focus on the mechanism of action and its possible therapeutic use in diseases characterized by insufficient angiogenesis.     

Circulatory bubble dynamics: From physical to biological aspects

Bubbles can form in the body during or after decompression from pressure exposures such as those undergone by scuba divers, astronauts, caisson and tunnel workers. Bubble growth and detachment physics then becomes significant in predicting and controlling the probability of these bubbles causing mechanical problems by blocking vessels, displacing tissues, or inducing an inflammatory cascade if they persist for too long in the body before being dissolved. By contrast to decompression induced bubbles whose site of initial formation and exact composition are debated, there are other instances of bubbles in the bloodstream which are well-defined. Gas emboli unwillingly introduced during surgical procedures and ultrasound microbubbles injected for use as contrast or drug delivery agents are therefore also discussed. After presenting the different ways that bubbles can end up in the human bloodstream, the general mathematical formalism related to the physics of bubble growth and detachment from decompression is reviewed. Bubble behavior in the bloodstream is then discussed, including bubble dissolution in blood, bubble rheology and biological interactions for the different cases of bubble and blood composition considered.     

PLLA/POSS Nanofibers Loaded with Multitargeted pANG Composite Nanoparticles for Promotion of Vascularization in Shear Flow

In vitro prevascularization is particularly important for the clinical application of tissue engineering scaffolds that require vascularization. The principal challenge is simulating the dynamic in vivo environment to promote the continuous growth of blood vessels. In this study, two targeting polypeptides are linked to the two ends of an amphiphilic block copolymer, polyethyleneimine‐b‐poly(lactide‐co‐3(S)‐methyl‐morpholine‐2,5‐dione)‐b‐polyethyleneimine (PEI‐PLMD‐PEI), and self‐assembled to form positively charged nanoparticles (NPs), which can bind to negatively charged pANG through electrostatic interactions; the polypeptides are finally loaded into PLLA/polyhedral oligomeric silsesquioxane (POSS) porous fibers to prepare untargeted nanofibers (unTFs), targeted porous nanofibers (TFBs), and targeted nanofiber bundles. The effects of the porous nanofibers on human umbilical vein endothelial cell (HUVEC) transfection, spreading, proliferation, morphology, and expression of related factors are investigated under the action of shear flow force. The results show that the PLLA/POSS nanofibers can maintain stable release of multitargeted NPs for nearly 45 days. Both the dual‐targeted porous NPs and shear flow improve the pANG transfection efficiency and promote cell proliferation, and they have a good synergistic effect. These results provide a potential strategy for designing HUVEC‐specific gene carriers and using shear flow to enhance endothelialization.     

Application of Chitosan-Based Biomaterials for Blood Vessel Regeneration

Summary: Vascular diseases are the leading cause of morbidity and mortality in the western world. Autologous vessels remain the standard for coronary grafting and peripheral bypass surgery; however, their availability in patients can be limited. Therapeutic angiogenesis using growth factors, genes, or progenitor cells has been given considerable scientific attention over the last decade, but has not yet provided a definitive clinical benefit. Biomaterials could be developed to protect protein, DNA and cells against hostile conditions. Chitosan, a natural polymer of glucosamine and N-acetyl glucosamine, has been widely studied in tissue engineering due to its biocompatibility, biodegradability, and muco-adhesive and antimicrobial properties. Notably, the application of chitosan has been gaining attention in the vascular field due to its structural similarity to glycosaminoglycans, which are components of a tissue's extracellular matrix. In this review, chitosan-based materials, and their use in tissue engineered blood vessels, and as protein, gene and cell vectors for angiogenic therapy are discussed.     

Myofibroblasts in the infarct area: concepts and challenges

Myofibroblasts are differentiated fibroblasts that hold a key role in wound healing and remodeling following myocardial infarction (MI). A large repertoire of stimuli, such as mechanical stretch, growth factors, cytokines, and vasoactive peptides, induces myofibroblast differentiation. Myofibroblasts are responsible for the production and deposition of collagen, leading to the establishment of a dense extracellular matrix that strengthens the infarcted tissue and minimizes dilatation of the infarct area. In addition, cells contributing to fibrosis act on sites distal from the infarct area and promote collagen deposition in noninfarcted tissue, thus contributing to adverse remodeling and consequently to the development of congestive heart failure (CHF). Current drugs that are used to treat post-MI CHF do influence fibroblasts and myofibroblasts; however, their therapeutic efficacy is far from being regarded as ideal. Novel therapeutic agents targeting (myo)fibroblasts are being developed to successfully prevent the cardiac remodeling of sites remote from the infarct area and therefore hinder the establishment of CHF. The purpose of this review article is to discuss the basic concepts of the myofibroblasts' actions in cardiac wound healing processes, factors that influence them, currently available pharmacological agents, and future challenges in this area.     

同轴电纺超细纤维膜构建人工血管材料

以右旋糖酐(DEX)为芯、聚乙二醇-b-聚(L-丙交酯-co-ε-己内酯)(PELCL)为壳,经同轴电纺制备DEX/PELCL超细纤维膜。在该电纺纤维内芯分别负载血管内皮生长因子(VEGF)和血小板衍生生长因子(PDGF-bb),并以此构建双层超细纤维膜人工血管支架。4 w的释放结果表明,VEGF和PDGF-bb均表现出突释现象,含有肝素的VEGF样品释放量有所下降。大鼠腹主动脉移植实验表明,载有VEGF和PDGF-bb的超细纤维膜可以用于构建双层人工血管。     

Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8⁺ T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8⁺ T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as T_H2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8⁺ T and CD4⁺ T_H1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.Subject terms: Cancer immunotherapy, Cancer microenvironment, Tumour angiogenesis, Tumour immunology, Targeted therapies     

Influence of specimen geometry on the slow crack growth testing of HDPE for pipe applications

The majority of field failures in piping are attributable to slow crack growth (SCG) fractures. These fractures are characterized by the stable growth of a crack with little deformation in the plastic material. Slow crack growth (SCG) testing involves accelerating the growth mechanism through elevated temperature, concentrated stress, constrained geometry, surfactants or some combination of these factors. Some of these accelerated tests, Pennsylvania Edge-Notch Tensile (PENT) and Full Notch Creep Tests (FNCT), have been designed specifically to promote the SCG failure by stress concentration. However, the development of new polymeric materials used in pipes for transportation, has greatly increased the time required to happen SCG failure through these accelerated tests. Recently, new specific geometries for specimens to promote the failure by SCG have been analyzed, such as the Circumferentially Deep Notched Tensile (CDNT) sample.In this work, the reliability of the CDNT specimen to promote SCG failure on two types of ethylene copolymers was studied. The ligament surfaces after failure were analyzed to identify the SCG. The failure times were compared with those obtained on the same materials tested with a PENT geometry.     

Biodegradable elastomer for soft tissue engineering

In this work we present the synthesis of a biodegradable, elastomeric material with a wide range of mechanical properties. The synthesis of the material was done by condensation polymerization of malic acid and 1,12–dodecandiol. The synthesized materials have low Young’s modulus ranging from about 1 to 4 MPa and a high elongation at break of 25–737% depending on the crosslinking density of the system. The cell growth observed under microscope showed good proliferation at 3 days of culture indicating good biocompatibility and support of L929 cells growth. The fabrication of 3D scaffold from these materials using the super critical CO₂ foaming method was also attempted. This method of scaffold fabrication is appropriate for materials that are easily hydrolysable and it also has the advantage of being a solvent free process. These materials are generally soft, biocompatible and biodegradable making them suitable for tissue engineering of soft tissues that are elastic in nature like muscles and blood vessels.     

FT-IR spectral imaging of blood vessels reveals protein secondary structure deviations induced by tumor growth

Vascular basement membrane remodeling is involved in tumor angiogenesis to enable tumor invasion and growth. FT-IR spectral imaging was used to determine changes in tumor blood vessels to reveal protein secondary structure in Rag-gamma immuno-deficient mice sacrificed 14 and 21 days after subcutaneous glioma implantation. For the oldest blood capillaries (diameter >20 microns), tumor growth induced a decrease in triple-helix content (1638 cm(-1); -7.3%; P < 0.05) and an increase in beta turns (1666 and 1615 cm(-1); +4%; P < 0.01). These protein-structure alterations, mainly from type IV collagen, reflected the high angiogenic stress of growing tumors. We propose to use these molecular markers of vascular basement membrane protein alterations for gradation of solid tumors by FT-IR spectral imaging.     

Advances in Mechanical Properties of Hydrogels for Cartilage Tissue Defect Repair

Numerous factors, such as degeneration and accidents, frequently cause cartilage deterioration. Owing to the absence of blood vessels and nerves in cartilage tissue, the ability of cartilage tissue to heal itself after an injury is relatively low. Hydrogels are beneficial for cartilage tissue engineering owing to their cartilage-like structure and advantageous properties. Due to the disruption of its mechanical structure, the bearing capacity and shock absorption of cartilage are diminished. The tissue should possess excellent mechanical properties to ensure the efficacy of cartilage tissue repair. This paper discusses the application of hydrogels in the fields of cartilage repair, the mechanical properties of hydrogels used for cartilage repair, and the materials used for hydrogels in cartilage tissue engineering. In addition, the challenges faced by hydrogels and future research directions are discussed.     

Design,Preparation, and Performance of a Novel Bilayer Tissue‐Engineered Small‐Diameter Vascular Graft

In clinical practice, the need for small‐diameter vascular grafts continues to increase. Decellularized xenografts are commonly used for vascular reconstructive procedures. Here, porcine coronary arteries are decellularized, which destroys the extracellular matrix structure, leading to the decrease of vascular strength and the increase of vascular permeability. A bilayer tissue‐engineered vascular graft (BTEV) is fabricated by electrospinning poly(l ‐lactide‐co‐carprolactone)/gelatin outside of the decellularized vessels and functionalized by immobilizing heparin, which increases the biomechanical strength and anticoagulant activity of decellularized vessels. The biosafety and efficacy of the heparin‐modified BTEVs (HBTEVs) are verified by implanting in rat models. HBTEVs remain patent and display no expansion or aneurism. After 4 weeks of implantation, a cell monolayer in the internal surface and a dense middle layer have formed, and the mechanical properties of regenerated vessels are similar to those of rat abdominal aorta. Therefore, HBTEVs can be used for rapid remodeling of small‐diameter blood vessels.     

Nitric Oxide: Chemical Puzzles Posed by a Biological Messenger

Recent years have seen a massive growth of interest in the biological effects of nitric oxide (NO): It acts as a signaling molecule in blood vessels and the brain, and as a defense against pathogens in the immune system. Discussed are the chemical events underlying the physiology of this versatile little molecule.     

Hemodynamics and Wall Shear Stress of Blood Vessels in Aortic Coarctation with Computational Fluid Dynamics Simulation

The purpose of this study was to identify the characteristics of blood flow in aortic coarctation based on stenotic shape structure, stenosis rate, and the distribution of the wall load delivered into the blood vessels and to predict the impact on aneurysm formation and rupture of blood vessels by using a computational fluid dynamics modeling method. It was applied on the blood flow in abdominal aortic blood vessels in which stenosis occurred by using the commercial finite element software ADINA on fluid-solid interactions. The results of modeling, with an increasing stenosis rate and Reynolds number, showed the pressure drop was increased and the velocity was greatly changed. When the stenosis rate was the same, the pressure drop and the velocity change were larger in the stenosis with a symmetric structure than in the stenosis with an asymmetric one. Maximal changes in wall shear stress were observed in the area before stenosis and minimal changes were shown in stenosis areas. The minimal shear stress occurred at different locations depending on the stenosis shape models. With an increasing stenosis rate and Reynolds number, the maximal wall shear stress was increased and the minimal wall shear stress was decreased. Through such studies, it is thought that the characteristics of blood flow in the abdominal aorta where a stenosis is formed will be helpful in understanding the mechanism of growth of atherosclerosis and the occurrence and rupture of the abdominal aortic flow.     

Rheological studies on blood coagulation and network formation of fibrin

Rheological studies on blood coagulation are summarized. The network structure of fibrin clots formed under different conditions is discussed from the kinetic analysis of the change of dynamic rigidity modulus during coagulation. The rheological properties of fibrin clots are shown. The effects of biochemical factors such as platelets, Factor XIII-mediated crosslinks and fibrinolysis on the viscoelasticity of blood during coagulation are also shown.In addition, it will be shown that rheological techniques make it possible to analyse the initial coagulation reaction of blood in contact with foreign surfaces such as collagen, cultured endothelial cells and artificial vascular vessels.     

Three-dimensional model of biomatrix as a method of studying blood vessels and nerve growth in tissue engineering structures

The method involves isolating and culturing ex vivo cultures of mouse dorsal root ganglia and abdominal aorta in a three-dimensional gel (Matrigel). Unlike other explant cultures, this technique allows to study the physiological and biochemical processes in the tissue explants of dorsal root ganglia and abdominal aorta in three-dimensional space but in contrast to a two-dimensional adhesive culture. Administration of the tested substances to the Matrigel allows analyzing their effects on the growth of blood vessels and neurites from the explants for 21 days. The developed method can be applied in modern cardiological and neurobiological research and explores how new therapeutic agents can accelerate the regeneration of blood vessels and nerves.     

Stimulation of human vascular endothelial cell growth by a platelet-derived growth factor and thrombin

Repair of a vascular wound is mediated by migration and subsequent replication of the endothelial cells that form the inner lining of blood vessels. We have measured the growth response of human umbilical vein endothelial cells (HuE) to two polypeptides that are transiently produced in high concentrations at the site of a wound; the platelet-derived growth factor (PDGF) and the protease thrombin. When 10(4) HuE cells are seeded as a dense island (2-mm diameter) in the center of a 16-mm tissue culture well in medium containing 20% human serum derived from platelet-poor plasma (PDS), no increase in cell number or colony size is observed. With the addition of 0.5 ng/ml partially purified PDGF, colony size increases and the number of cells after 8 days is 4.8 X 10(4). When human thrombin (1 microgram/ml) is added along with the PDGF, the cell number rises to 9.2 X 10(4). Thrombin alone stimulates no increase in cell number. Although partially purified PDGF stimulates endothelial cells maintained in PDS as well as those maintained in whole blood serum (WBS), pure PDGF is active only when assayed in medium that contains WBS and is supplemented with thrombin. These results suggest the existence of a second class of platelet-derived factors that enable HuE cells to respond to the mitogenic activity of the purified platelet mitogen and thrombin.     

Promotion of <Emphasis Type="Italic">α</Emphasis>-cyano-4-hydroxycinnamic acid and peptide cocrystallization within levitated droplets with net charge

Many reactions occur as a result of charge imbalance within or between reactive species in reaction vessels that have zero net charge. Here, chemical processes taking place within reaction vessels having net excess charge were studied. For mass spectroscopists, a familiar example of vessels that defy electroneutrality are the charged droplets produced by an electrospray ion source. Evidence is presented that control of the magnitude of the net charge contained in a reaction vessel, in this case a levitated droplet, can be used to promote nucleation and crystal growth of a mixture of an organic acid, alpha-cyano-4-hydroxycinnamic acid (CHCA), with one or more peptides. This phenomenon was first observed during our ongoing development of wall-less sample preparation (WaSP), electrodynamic charged droplet processing methodology capable of creating micrometer-sized sample spots for matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) from subnanoliter volumes of sample material. Peptide ion signal-to-noise (S/N) ratios obtained by MALDI-TOF-MS from sample spots created from droplets that had high relative magnitude of net charge were consistently greater than those detected from sample spots created from droplets that had lower net charge. To study this unexpected phenomenon further, WaSP methodology was developed to process different mass-to-charge (m/z) droplets levitated in an electrodynamic balance (EDB), facilitating their deposition onto different positions of a target to create arrays of droplet residues ordered from highest to lowest m/z. This capability allowed simultaneous levitation with subsequent separation of a population of droplets created from a single starting solution, but the droplets had varied magnitudes of net charge. After the droplets were ejected from the EDB and collected on a glass slide or MALDI plate, the solids contained in the deposited droplets were characterized using microscopy and MALDI-TOF-MS. Factors impacting the chemical processing in droplets having net excess charge levitated in an EDB are discussed with particular emphasis on their possible roles in the promotion of crystal nucleation and growth.     

The Synthetic Strategy toward of ACE-Inhibitors

Angiotensin II is an important octapeptide which is responsible for the increase in blood pressure in three major mechanisms. It acts as a hormone to attack the receptor on the blood vessels, which cause strong vasoconstriction. It is also the major stimulus for release another hormone, aldolsterone, which promote the excretion of potassium ion and retention of sodium and waster. Both of the above effects increase the blood pressure. On the other hand, ACE (Angiotensin Converting Enzyme) catalyzes the hydrolysis of bradykinin that is a potent vasodilator. Therefore, the inhibitor of ACE can act as an efficient anti-hypertensive agent through multiple routes.     

Morphological changes in blood vessels produced by hyperosmotic agents and measured by optical coherence tomography

Optical tissue clearing by hyperosmotic chemical agents significantly increases light depth penetration in skin and may improve light-based therapeutics such as laser treatment of cutaneous vascular lesions. A feasibility study was conducted to evaluate the potential role of optical clearing by glycerol in laser treatment of cutaneous vessels. Optical imaging was performed to investigate the morphological effects of glycerol on blood vessels of skin. Blood vessels were imaged using Doppler optical coherence tomography in in vivo hamster skin treated with glycerol. Images were obtained from the subdermal side to assess morphological changes in the blood vessels caused by glycerol and from the epidermal side to assess enhanced Doppler imaging of blood vessels. Application of glycerol to the subdermis resulted in venule stasis and for prolonged treatment times, arteriole stasis. In cases where flow remained in arterioles, an improved Doppler signal was detected from blood vessels when imaging transepidermally compared with the native condition. Intensity images indicated changes in blood optical properties and improved contrast of skin cross sections after glycerol application. The observed optical and morphological effects were reversed upon hydration of the skin with phosphate-buffered saline. The combination of increased depth of light penetration and the temporary slowing or cessation of flow in blood vessels could mean improved laser treatment of vessels.