Rupture In Response Research Articles

Abstract 525: Angiotensin Ii Type 1a Receptor Deletion In Vascular Smooth Muscle Cells Prevent Abdominal Aortic Aneurysm Formation Induced By Angiotensin Ii Plus β-aminopropionitrile

Abdominal aortic aneurysm (AAA) is multifactorial disease resulting from changes in the aortic wall structure, such as medial degradation and inflammation, causing life-threatening AAA rupture. Angiotensin II (AngII) type 1A receptor (AT 1A R) upon AngII binding mediates blood pressure elevation and several chronic cardiovascular diseases including AAA. Treatment with AngII plus β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, in normolipidemic C57BL6 mice similarly induces AAA. However, we have limited understanding whether smooth muscle AT 1A R affects AAA formation induced by AngII plus BAPN. Thus, the subject of this study is to test the contribution of smooth muscle AT 1A R to AngII-dependent AAA development in normocholesterolemic mice. At 8 to 12 week of age, smooth muscle AT 1A R silenced mice (knock-in Tagln-Cre +/- crossed with AT 1A R flox/flox mice) and control mice were infused with AngII (1 μg/kg/min) via osmotic mini-pump for 4 weeks and treated with 1 g/L BAPN containing water for the first 2 weeks or sham-operated for mini-pump implantation. After 4 weeks, significant increases in maximum external aortic diameter and structural alterations were observed in the control mice, which was attenuated in smooth muscle AT 1A R silenced mice (1.67 mm vs. 1.22 mm, p<0.05). AngII plus BAPN treatment increased perivascular collagen III positive cell ratio, which was normalized in smooth muscle AT 1A R silenced mice (p<0.01). Evaluation of blood pressure at week 4 in conscious mice showed significant reduction in AngII-induced hypertension in smooth muscle AT 1A R silenced mice (p<0.01). Furthermore, in contrast to control mice, no death duet to aortic rupture was observed in smooth muscle AT 1A R silenced mice. In conclusion, our study has demonstrated the significant contribution of smooth muscle expressing AT 1A R in mediating AAA development and rupture in response to AngII plus BAPN treatment. It is possible that attenuation of hypertension in the AT 1A R silenced mice may provide additional protection against AAA rupture.

Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation

Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/−) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.

Assembly of Graphene Platelets for Bioinspired, Stimuli-Responsive, Low Ice Adhesion Surfaces.

Design and fabrication of functional materials for anti-icing and deicing attract great attention from both the academic research and industry. Among them, the study of fish-scale-like materials has proved that enabling sequential rupture is an effective approach for weakening the intrinsic interface adhesion. Here, graphene platelets were utilized to construct fish-scale-like surfaces for easy ice detachment. Using a biomimicking arrangement of the graphene platelets, the surfaces were able to alter their structural morphology for the sequential rupture in response to external forces. With different packing densities of graphene platelets, all the surfaces showed universally at least 50% reduction in atomistic tensile ice adhesion strength. Because of the effect of sequential rupture, stronger ice–surface interactions did not lead to an obvious increase in ice adhesion. Interestingly, the high packing density of graphene platelets resulted in stable and reversible surface morphology in cyclic tensile and shearing tests, and subsequently high reproducibility of the sequential rupture mode. The fish-scale-like surfaces built and tested, together with the nanoscale deicing results, provided a close view of ice adhesion mechanics, which can promote future bioinspired, stress-responsive, anti-icing surface designs.

Rumpel-Leede phenomenon after brachial artery catheterization

Background: Rumpel-Leede (R-L) phenomenon is a rare event in which the small dermal capillaries of an extremity rupture in response to application of mechanical pressure to that extremity, such as when inflating a cuff during noninvasive blood pressure monitoring , when tying a tourniquet to draw blood or when applying compressive devices to the arm arteries following heart catheterization. Case presentation: In this report, we present an interesting case of a patient who develops Rumpel-Leede phenomenon, characterized by the appearance of a petechial rash that results from acute dermal capillary rupture that occurred secondary to raised pressure in the dermal vessels caused by the inflation of a compression device at the brachial artery site post coronary angioplasty. Conclusion: This report highlighted the importance of considering the Rumpel-Leed phenomenon as a benign and self-limited condition in patient who develops a petechial rash following compression of the upper extremity arteries.

Polymeric encapsulation of liquids via plasma surface polymerization

ABSTRACTThis study introduces a new approach of liquid encapsulation using an atmospheric pressure plasma (APP). The technique is similar to interfacial polymerization, though here one phase is liquid (that contains unsaturated C═C bonds) and the other phase is plasma (that contains free radicals). When combined, the atmospheric plasma can induce surface polymerization of an acrylate‐based liquid, resulting in a thin polymeric skin on top of the liquid. Measurements with an atomic force microscope and a spectroscopic ellipsometer estimate the thickness of the skin formed on top of di(ethylene glycol) diacrylate to be 40–50 nm. To demonstrate an application of this method, we encapsulated hemispherical capsules of reactive adhesives on a glass substrate. These adhesives are based on thiol‐acrylate and thiol‐acrylate‐epoxy systems that react in the presence of a strong base catalyst. Plasma‐induced polymerization can encapsulate, immobilize, and isolate separate droplets of resin and the catalyst in a latent (nonreactive) state. These capsules remain latent until they rupture in response to physical contact. A tensile testing machine reports an adhesive strength of ~ 2 MPa for the formulated resins after curing. The capsules reported here may be useful for storing functional liquids for just‐in‐time release, such as contact‐sensitive adhesives, on‐demand lubricants, or self‐healing agents. © 2020 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48880.

LNK deficiency promotes acute aortic dissection and rupture.

Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.

Invited commentary

Invited commentary

Mitochondria Targeting Non-Isocyanate-Based Polyurethane Nanocapsules for Enzyme-Triggered Drug Release.

Surface engineering of nanocarriers allows fine-tuning of their interactions with biological organisms, potentially forming the basis of devices for the monitoring of intracellular events or for intracellular drug delivery. In this context, biodegradable nanocarriers or nanocapsules capable of carrying bioactive molecules or drugs into the mitochondrial matrix could offer new capabilities in treating mitochondrial diseases. Nanocapsules with a polymeric backbone that undergoes programmed rupture in response to a specific chemical or enzymatic stimulus with subsequent release of the bioactive molecule or drug at mitochondria would be particularly attractive for this function. With this goal in mind, we have developed biologically benign nanocapsules using polyurethane-based, polymeric backbone that incorporates repetitive ester functionalities. The resulting nanocapsules are found to be highly stable and monodispersed in size. Importantly, a new non-isocyanate route is adapted for the synthesis of these non-isocyanate polyurethane nanocapsules (NIPU). The embedded ester linkages of these capsules' shells have facilitated complete degradation of the polymeric backbone in response to a stimulus provided by an esterase enzyme. Hydrophilic payloads like rhodamine or doxorubicin can be loaded inside these nanocarriers during their synthesis by an interfacial polymerization reaction. The postgrafting of the nanocapsules with phosphonium ion, a mitochondria-targeting receptor functionality, has helped us achieve the site-specific release of the drug. Co-localization experiments with commercial mitotracker green as well as mitotracker deep red confirmed localization of the cargo in mitochondria. Our in vitro studies confirm that specific release of doxorubicin within mitochondria causes higher cytotoxicity and cell death compared to free doxorubicin. Endogenous enzyme triggered nanocapsule rupture and release of the encapsulated dye is also demonstrated in a zebrafish model. The results of this proof-of-concept study illustrate that NIPU nanocarriers can provide a site-specific delivery vehicle and improve the therapeutic efficacy of a drug or be used to produce organelle-specific imaging studies.

Aesthetic ruptures: viewing graffiti as the emplaced vernacular

ABSTRACTThis essay theorizes the notion of the emplaced vernacular, a type of vernacular expression that is mobilized by the production of aesthetics in particular places. I argue that 1970s graffiti in New York City emerged as an aesthetic rupture in response to the spatial exigencies of postwar urban renewal projects. Analysis of The New York Times coverage of graffiti writers “Kilroy was Here” from WWII and “Taki 183” from the 1970s demonstrates how the force of this emplaced vernacular was disciplined within dominant spatial ideologies, producing an aesthetic that continues to enable and constrain contemporary efforts of vernacular subjectification.

New perspectives on ACL injury: On the role of repetitive sub-maximal knee loading in causing ACL fatigue failure.

ABSTRACTIn this paper, we review a series of studies that we initiated to examine mechanisms of anterior cruciate ligament (ACL) injury in the hope that these injuries, and their sequelae, can be better prevented. First, using the earliest in vitro model of a simulated single‐leg jump landing or pivot cut with realistic knee loading rates and trans‐knee muscle forces, we identified the worst‐case dynamic knee loading that causes the greatest peak ACL strain: Combined knee compression, flexion, and internal tibial rotation. We also identified morphologic factors that help explain individual susceptibility to ACL injury. Second, using the above knee loading, we introduced a possible paradigm shift in ACL research by demonstrating that the human ACL can fail by a sudden rupture in response to repeated sub‐maximal knee loading. If that load is repeated often enough over a short time interval, the failure tended to occur proximally, as observed clinically. Third, we emphasize the value of a physical exam of the hip by demonstrating how limited internal axial rotation at the hip both increases the susceptibility to ACL injury in professional athletes, and also increases peak ACL strain during simulated pivot landings, thereby further increasing the risk of ACL fatigue failure. When training at‐risk athletes, particularly females with their smaller ACL cross‐sections, rationing the number and intensity of worst‐case knee loading cycles, such that ligament degradation is within the ACL's ability to remodel, should decrease the risk for ACL rupture due to ligament fatigue failure.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:2059–2068, 2016.

Rumpel-Leede Phenomenon Presenting as a Hypertensive Urgency

Rumpel-Leede (R-L) phenomenon is the rare event in which the small dermal capillaries of an extremity rupture in response to application of a compressive device to that extremity, such as when inflating a cuff during noninvasive blood pressure monitoring or when applying a tourniquet to draw blood. This capillary rupture results in formation of a petechial rash distal to the compressive device. R-L phenomenon is believed to occur most often in patients with underlying vascular disease, such as diabetes mellitus or thrombocytopenia. R-L phenomenon is most often benign, though it may rarely be associated with pain and discomfort. There is no treatment for this condition apart from treatment of the underlying vascular disease or thrombocytopenia. We report a 57-year-old woman who presented with hypertensive urgency and experienced R-L phenomenon during blood pressure cuff inflation.

Modulation of Kinin B2 Receptor Signaling Controls Aortic Dilatation and Rupture in the Angiotensin II-Infused Apolipoprotein E-Deficient Mouse.

Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein-kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. AAA was induced in apolipoprotein E-deficient mice via infusion of angiotensin II (1.0 μg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II-induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II-induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 μg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.

An Endosperm-Associated Cuticle Is Required for Arabidopsis Seed Viability, Dormancy and Early Control of Germination.

Cuticular layers and seeds are prominent plant adaptations to terrestrial life that appeared early and late during plant evolution, respectively. The cuticle is a waterproof film covering plant aerial organs preventing excessive water loss and protecting against biotic and abiotic stresses. Cutin, consisting of crosslinked fatty acid monomers, is the most abundant and studied cuticular component. Seeds are dry, metabolically inert structures promoting plant dispersal by keeping the plant embryo in an arrested protected state. In Arabidopsis thaliana seeds, the embryo is surrounded by a single cell endosperm layer itself surrounded by a seed coat layer, the testa. Whole genome analyses lead us to identify cutin biosynthesis genes as regulatory targets of the phytohormones gibberellins (GA) and abscisic acid (ABA) signaling pathways that control seed germination. Cutin-containing layers are present in seed coats of numerous species, including Arabidopsis, where they regulate permeability to outer compounds. However, the role of cutin in mature seed physiology and germination remains poorly understood. Here we identify in mature seeds a thick cuticular film covering the entire outer surface of the endosperm. This seed cuticle is defective in cutin-deficient bodyguard1 seeds, which is associated with alterations in endospermic permeability. Furthermore, mutants affected in cutin biosynthesis display low seed dormancy and viability levels, which correlates with higher levels of seed lipid oxidative stress. Upon seed imbibition cutin biosynthesis genes are essential to prevent endosperm cellular expansion and testa rupture in response to low GA synthesis. Taken together, our findings suggest that in the course of land plant evolution cuticular structures were co-opted to achieve key physiological seed properties.

Sequential release of nanoparticle payloads from ultrasonically burstable capsules

In many biomedical contexts ranging from chemotherapy to tissue engineering, it is beneficial to sequentially present bioactive payloads. Explicit control over the timing and dose of these presentations is highly desirable. Here, we present a capsule-based delivery system capable of rapidly releasing multiple payloads in response to ultrasonic signals. In vitro, these alginate capsules exhibited excellent payload retention for up to 1 week when unstimulated and delivered their entire payloads when ultrasonically stimulated for 10–100 s. Shorter exposures (10 s) were required to trigger delivery from capsules embedded in hydrogels placed in a tissue model and did not result in tissue heating or death of encapsulated cells. Different types of capsules were tuned to rupture in response to different ultrasonic stimuli, thus permitting the sequential, on-demand delivery of nanoparticle payloads. As a proof of concept, gold nanoparticles were decorated with bone morphogenetic protein-2 to demonstrate the potential bioactivity of nanoparticle payloads. These nanoparticles were not cytotoxic and induced an osteogenic response in mouse mesenchymal stem cells. This system may enable researchers and physicians to remotely regulate the timing, dose, and sequence of drug delivery on-demand, with a wide range of clinical applications ranging from tissue engineering to cancer treatment.

IL-1α induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs.

Intravital visualization of thrombopoiesis revealed that formation of proplatelets, which are cytoplasmic protrusions in bone marrow megakaryocytes (MKs), is dominant in the steady state. However, it was unclear whether this is the only path to platelet biogenesis. We have identified an alternative MK rupture, which entails rapid cytoplasmic fragmentation and release of much larger numbers of platelets, primarily into blood vessels, which is morphologically and temporally different than typical FasL-induced apoptosis. Serum levels of the inflammatory cytokine IL-1α were acutely elevated after platelet loss or administration of an inflammatory stimulus to mice, whereas the MK-regulator thrombopoietin (TPO) was not elevated. Moreover, IL-1α administration rapidly induced MK rupture-dependent thrombopoiesis and increased platelet counts. IL-1α-IL-1R1 signaling activated caspase-3, which reduced plasma membrane stability and appeared to inhibit regulated tubulin expression and proplatelet formation, and ultimately led to MK rupture. Collectively, it appears the balance between TPO and IL-1α determines the MK cellular programming for thrombopoiesis in response to acute and chronic platelet needs.

IL-1[alpha] induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs

IL-1[alpha] induces thrombopoiesis through megakaryocyte rupture in response to acute platelet needs

Seismic precursors linked to highly compressible fluids at oceanic transform faults

Earthquakes on oceanic transform faults are often preceded by foreshock swarms. A theoretical model suggests that circulating hydrothermal fluids, which compress as the fault rocks expand and deform, cause this precursor seismic activity. Large earthquakes on mid-ocean ridge transform faults are commonly preceded by foreshocks1,2,3 and changes in the seismic properties of the fault zone3. These seismic precursors could be linked to fluid-related processes2,3. Hydrothermal fluids within young, hot crust near the intersection of oceanic transform faults become significantly more compressible with decreasing pressure, with potential impacts on fault behaviour. Here we use a theoretical model to show that oceanic transform faults can switch from dilatant and progressive deformation to rupture in response to fluid-related processes. We assume that the fault core material behaves according to a dilatant and strain-softening or contractant and strain-hardening constitutive law (Cam-clay-type4), depending on the effective stress state. According to our model, after the initial purely rigid-elastic phase, dilatancy is found to occur within the fault core, causing pore pressure to decrease, hence fluid compressibility to increase. The plastic regime starts with a stable phase, with effective stresses gradually increasing over a timescale of years in response to tectonic loading. The fault then evolves into a metastable phase, lasting a few days, as the pore pressure decreases, inducing large variations or even a discontinuous jump in fluid compressibility, depending on fluid properties. This in turn triggers fault-slip instability that creates foreshock swarms. In the final phase, the fault fails in the mainshock rupture. Our results imply that seismic precursors are caused by the decrease in fluid pressure which results in an increase in fluid compressibility, in response to fault core dilatancy just before rupture.

Arterial stiffness in patients with deep and lobar intracerebral hemorrhage.

Background and PurposeIntracerebral hemorrhage (ICH) accounts for approximately 10% of stroke cases. Hypertension may play a role in the pathogenesis of ICH that occurs in the basal ganglia, thalamus, pons, and cerebellum, but not in that of lobar ICH. Hypertension contributes to decreased elasticity of arteries, thereby increasing the likelihood of rupture in response to acute elevation in intravascular pressure. This study aimed to evaluate arterial stiffness (using the arterial stiffness index [ASI]) in patients with deep (putaminal and thalamic) ICH in comparison with patients with lobar ICH.MethodsWe enrolled 64 patients (mean±SD age: 69.3±10.7 years; 47 men and 17 women) among 73 who referred consecutively to our department for intraparenchymal hemorrhage and underwent brain computed tomography (CT) and cerebral angio-CT. In all the subjects, 24-hour heart rates and blood pressures were monitored. The linear regression slope of diastolic on systolic blood pressure was assumed as a global measure of arterial compliance, and its complement (1 minus the slope), ASI, has been considered as a measure of arterial stiffness.ResultsIn the patients with deep ICH, ASI was significantly higher than in the patients with lobar ICH (0.64±0.19 vs. 0.53±0.17, P=0.04).ConclusionsOur results suggest that in deep ICH, arterial stiffening represents a possible pathogenetic factor that modifies arterial wall properties and contributes to vascular rupture in response to intravascular pressure acute elevation. Therapeutic strategies that reduce arterial stiffness may potentially lower the incidence of deep hemorrhagic stroke.

Changes in Cytosolic ATP Levels and Intracellular Morphology during Bacteria-Induced Hypersensitive Cell Death as Revealed by Real-Time Fluorescence Microscopy Imaging

Hypersensitive cell death is known to involve dynamic remodeling of intracellular structures that uses energy released during ATP hydrolysis. However, the relationship between intracellular structural changes and ATP levels during hypersensitive cell death remains unclear. Here, to visualize ATP dynamics directly in real time in individual living plant cells, we applied a genetically encoded Förster resonance energy transfer (FRET)-based fluorescent ATP indicator, ATeam1.03-nD/nA, for plant cells. Intracellular ATP levels increased approximately 3 h after inoculation with the avirulent strain DC3000/avrRpm1 of Pseudomonas syringae pv. tomato (Pst), which was accompanied by the simultaneous disappearance of transvacuolar strands and appearance of bulb-like structures within the vacuolar lumen. Approximately 5 h after bacterial inoculation, the bulb-like structures disappeared and ATP levels drastically decreased. After another 2 h, the large central vacuole was disrupted. In contrast, no apparent changes in intracellular ATP levels were observed in the leaves inoculated with the virulent strain Pst DC3000. The Pst DC3000/avrRpm1-induced hypersensitive cell death was strongly suppressed by inhibiting ATP synthesis after oligomycin A application within 4 h after bacterial inoculation. When the inhibitor was applied 7 h after bacterial inoculation, cell death was unaffected. These observations show that changes in intracellular ATP levels correlate with intracellular morphological changes during hypersensitive cell death, and that ATP is required just before vacuolar rupture in response to bacterial infection.

Multi-scale simulation of L-selectin–PSGL-1-dependent homotypic leukocyte binding and rupture

L-selectin-PSGL-1-mediated polymorphonuclear (PMN) leukocyte homotypic interactions potentiate the extent of PMN recruitment to endothelial sites of inflammation. Cell-cell adhesion is a complex phenomenon involving the interplay of bond kinetics and hydrodynamics. As a first step, a 3-D computational model based on the Immersed Boundary Method is developed to simulate adhesion-detachment of two PMN cells in quiescent conditions. Our simulations predict that the total number of bonds formed is dictated by the number of available receptors (PSGL-1) when ligands (L-selectin) are in excess, while the excess amount of ligands influences the rate of bond formation. Increasing equilibrium bond length results in a higher number of receptor-ligand bonds due to an increased intercellular contact area. On-rate constants determine the rate of bond formation, while off-rates control the average number of bonds by modulating bond lifetimes. Application of an external pulling force leads to time-dependent on- and off-rates and causes bond rupture. Moreover, the time required for bond rupture in response to an external force is inversely proportional to the applied load and decreases with increasing off-rate.