Publications by authors named "Sheldon Weinbaum"

58 Publications

Nanoanalytical analysis of bisphosphonate-driven alterations of microcalcifications using a 3D hydrogel system and in vivo mouse model.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

Vascular calcification predicts atherosclerotic plaque rupture and cardiovascular events. Retrospective studies of women taking bisphosphonates (BiPs), a proposed therapy for vascular calcification, showed that BiPs paradoxically increased morbidity in patients with prior acute cardiovascular events but decreased mortality in event-free patients. Calcifying extracellular vesicles (EVs), released by cells within atherosclerotic plaques, aggregate and nucleate calcification. We hypothesized that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the risk of plaque rupture. Three-dimensional (3D) collagen hydrogels incubated with calcifying EVs were used to mimic fibrous cap calcification in vitro, while an ApoE mouse was used as a model of atherosclerosis in vivo. EV aggregation and formation of stress-inducing microcalcifications was imaged via scanning electron microscopy (SEM) and atomic force microscopy (AFM). In both models, BiP (ibandronate) treatment resulted in time-dependent changes in microcalcification size and mineral morphology, dependent on whether BiP treatment was initiated before or after the expected onset of microcalcification formation. Following BiP treatment at any time, microcalcifications formed in vitro were predicted to have an associated threefold decrease in fibrous cap tensile stress compared to untreated controls, estimated using finite element analysis (FEA). These findings support our hypothesis that BiPs alter EV-driven calcification. The study also confirmed that our 3D hydrogel is a viable platform to study EV-mediated mineral nucleation and evaluate potential therapies for cardiovascular calcification.
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http://dx.doi.org/10.1073/pnas.1811725118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040669PMC
April 2021

The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases.

Cardiovasc Eng Technol 2021 Feb 21;12(1):37-71. Epub 2020 Sep 21.

Biomedical Engineering Department, The City College of New York, New York, NY, USA.

Purpose: In 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121-167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper.

Methods: A literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases.

Results: In part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel-Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments.

Conclusion: As we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.
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http://dx.doi.org/10.1007/s13239-020-00485-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505222PMC
February 2021

S100A9-RAGE Axis Accelerates Formation of Macrophage-Mediated Extracellular Vesicle Microcalcification in Diabetes Mellitus.

Arterioscler Thromb Vasc Biol 2020 08 28;40(8):1838-1853. Epub 2020 May 28.

From the Center for Excellence in Vascular Biology (R.K., S.K., R.T., D.C.R., D.B.-G., L.S.A.P., G.K.S., P.L., M.A., K.C., E.A.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Objective: Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, <0.001) in macrophages. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. In addition, streptozotocin-induced diabetic ApoeS100a9 mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification.

Conclusions: Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within atherosclerotic plaques.
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http://dx.doi.org/10.1161/ATVBAHA.118.314087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377960PMC
August 2020

A Lifetime Achievement in Bioengineering: Professor Shu Chien.

Ann Biomed Eng 2019 11;47(11):2147-2150

Department of Bioengineering, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0412, USA.

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http://dx.doi.org/10.1007/s10439-019-02390-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838045PMC
November 2019

Microcalcifications, Their Genesis, Growth, and Biomechanical Stability in Fibrous Cap Rupture.

Adv Exp Med Biol 2018;1097:129-155

Department of Biomedical Engineering, The City College of New York, New York, NY, USA.

For many decades, cardiovascular calcification has been considered as a passive process, accompanying atheroma progression, correlated with plaque burden, and apparently without a major role on plaque vulnerability. Clinical and pathological analyses have previously focused on the total amount of calcification (calcified area in a whole atheroma cross section) and whether more calcification means higher risk of plaque rupture or not. However, this paradigm has been changing in the last decade or so. Recent research has focused on the presence of microcalcifications (μCalcs) in the atheroma and more importantly on whether clusters of μCalcs are located in the cap of the atheroma. While the vast majority of μCalcs are found in the lipid pool or necrotic core, they are inconsequential to vulnerable plaque. Nevertheless, it has been shown that μCalcs located within the fibrous cap could be numerous and that they behave as an intensifier of the background circumferential stress in the cap. It is now known that such intensifying effect depends on the size and shape of the μCalc as well as the proximity between two or more μCalcs. If μCalcs are located in caps with very low background stress, the increase in stress concentration may not be sufficient to reach the rupture threshold. However, the presence of μCalc(s) in the cap with a background stress of about one fifth to one half the rupture threshold (a stable plaque) will produce a significant increase in local stress, which may exceed the cap rupture threshold and thus transform a non-vulnerable plaque into a vulnerable one. Also, the classic view that treats cardiovascular calcification as a passive process has been challenged, and emerging data suggest that cardiovascular calcification may encompass both passive and active processes. The passive calcification process comprises biochemical factors, specifically circulating nucleating complexes, which would lead to calcification of the atheroma. The active mechanism of atherosclerotic calcification is a cell-mediated process via cell death of macrophages and smooth muscle cells (SMCs) and/or the release of matrix vesicles by SMCs.
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http://dx.doi.org/10.1007/978-3-319-96445-4_7DOI Listing
July 2019

Potential role for a specialized β integrin-based structure on osteocyte processes in bone mechanosensation.

J Orthop Res 2018 02 28;36(2):642-652. Epub 2017 Nov 28.

Department of Biomedical Engineering, The City College of New York, New York, New York.

Osteocyte processes are an order of magnitude more sensitive to mechanical loading than their cell bodies. The mechanisms underlying this remarkable mechanosensitivity are not clear, but may be related to the infrequent α β integrin sites where the osteocyte cell processes attach to canalicular walls. These sites develop dramatically elevated strains during load-induced fluid flow in the lacunar-canalicular system and were recently shown to be primary sites for osteocyte-like MLO-Y4 cell mechanotransduction. These α β integrin sites lack typical integrin transduction mechanisms. Rather, stimulation at these sites alters Ca signaling, ATP release and membrane potential. In the current studies, we tested the hypothesis that in authentic osteocytes in situ, key membrane proteins implicated in osteocyte mechanotransduction are preferentially localized at or near to β integrin-foci. We analyzed these spatial relationships in mouse bone osteocytes using immunohistochemistry combined with Structured Illumination Super Resolution Microscopy, a method that permits structural resolution at near electron microscopy levels in tissue sections. We discovered that the purinergic channel pannexin1, the ATP-gated purinergic receptor P2 × 7R and the low voltage transiently opened T-type calcium channel CaV3.2-1 all reside in close proximity to β integrin attachment foci on osteocyte processes, suggesting a specialized mechanotransduction complex at these sites. We further confirmed this observation on isolated osteocytes in culture using STochasitc Optical Resonance Microscopy. These findings identify a possible structural basis for the unique mechanosensation and transduction capabilities of the osteocyte process. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:642-652, 2018.
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http://dx.doi.org/10.1002/jor.23792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839970PMC
February 2018

Osteocyte calcium signals encode strain magnitude and loading frequency in vivo.

Proc Natl Acad Sci U S A 2017 10 19;114(44):11775-11780. Epub 2017 Oct 19.

Department of Biomedical Engineering, City College of New York, New York, NY 10031;

Osteocytes are considered to be the major mechanosensory cells of bone, but how osteocytes in vivo process, perceive, and respond to mechanical loading remains poorly understood. Intracellular calcium (Ca) signaling resulting from mechanical stimulation has been widely studied in osteocytes in vitro and in bone explants, but has yet to be examined in vivo. This is achieved herein by using a three-point bending device which is capable of delivering well-defined mechanical loads to metatarsal bones of living mice while simultaneously monitoring the intracellular Ca responses of individual osteocytes by using a genetically encoded fluorescent Ca indicator. Osteocyte responses are imaged by using multiphoton fluorescence microscopy. We investigated the in vivo responses of osteocytes to strains ranging from 250 to 3,000 [Formula: see text] and frequencies from 0.5 to 2 Hz, which are characteristic of physiological conditions reported for bone. At all loading frequencies examined, the number of responding osteocytes increased strongly with applied strain magnitude. However, Ca intensity within responding osteocytes did not change significantly with physiological loading magnitudes. Our studies offer a glimpse into how these critical bone cells respond to mechanical load in vivo, as well as provide a technique to determine how the cells encode magnitude and frequency of loading.
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http://dx.doi.org/10.1073/pnas.1707863114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676898PMC
October 2017

Regulation of glomerulotubular balance: flow-activated proximal tubule function.

Pflugers Arch 2017 06 7;469(5-6):643-654. Epub 2017 Mar 7.

Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, NY, USA.

The purpose of this review is to summarize our knowledge and understanding of the physiological importance and the mechanisms underlying flow-activated proximal tubule transport. Since the earliest micropuncture studies of mammalian proximal tubule, it has been recognized that tubular flow is an important regulator of sodium, potassium, and acid-base transport in the kidney. Increased fluid flow stimulates Na and HCO absorption in the proximal tubule via stimulation of Na/H-exchanger isoform 3 (NHE3) and H-ATPase. In the proximal tubule, brush border microvilli are the major flow sensors, which experience changes in hydrodynamic drag and bending moment as luminal flow velocity changes and which transmit the force of altered flow to cytoskeletal structures within the cell. The signal to NHE3 depends upon the integrity of the actin cytoskeleton; the signal to the H-ATPase depends upon microtubules. We have demonstrated that alterations in fluid drag impact tubule function by modulating ion transporter availability within the brush border membrane of the proximal tubule. Beyond that, there is evidence that transporter activity within the peritubular membrane is also modulated by luminal flow. Secondary messengers that regulate the flow-mediated tubule function have also been delineated. Dopamine blunts the responsiveness of proximal tubule transporters to changes in luminal flow velocity, while a DA1 antagonist increases flow sensitivity of solute reabsorption. IP3 receptor-mediated intracellular Ca signaling is critical to transduction of microvillus drag. In this review, we summarize our findings of the regulatory mechanism of flow-mediated Na and HCO transport in the proximal tubule and review available information about flow sensing and regulatory mechanism of glomerulotubular balance.
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http://dx.doi.org/10.1007/s00424-017-1960-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162058PMC
June 2017

Zooming in on the genesis of atherosclerotic plaque microcalcifications.

J Physiol 2016 06 1;594(11):2915-27. Epub 2016 May 1.

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Epidemiological evidence conclusively demonstrates that calcium burden is a significant predictor of cardiovascular morbidity and mortality; however, the underlying mechanisms remain largely unknown. These observations have challenged the previously held notion that calcification serves to stabilize the atherosclerotic plaque. Recent studies have shown that microcalcifications that form within the fibrous cap of the plaques lead to the accrual of plaque-destabilizing mechanical stress. Given the association between calcification morphology and cardiovascular outcomes, it is important to understand the mechanisms leading to calcific mineral deposition and growth from the earliest stages. We highlight the open questions in the field of cardiovascular calcification and include a review of the proposed mechanisms involved in extracellular vesicle-mediated mineral deposition.
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http://dx.doi.org/10.1113/JP271339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887667PMC
June 2016

Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques.

Nat Mater 2016 Mar 11;15(3):335-43. Epub 2016 Jan 11.

Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification areas. We also show that calcification morphology and the plaque's collagen content-two determinants of atherosclerotic plaque stability-are interlinked.
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http://dx.doi.org/10.1038/nmat4519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767675PMC
March 2016

Flow-activated proximal tubule function underlies glomerulotubular balance.

Kitasato Med J 2016 ;46(1):105-117

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT.

Flow-modulated salt and water transport in proximal tubules has been recognized for more than four decades. Recent work has made major progress in defining the underlying cellular mechanisms. First, we demonstrated that perfusion-absorption balance is present in the isolated perfused proximal tubule of the mouse kidney, and thus is independent of neuronal control and systemic hormonal regulation. In proximal tubule, higher axial flow rates stimulate sodium and bicarbonate absorption by increased apical membrane Na/H-transporter and H-ATPase activity. It is also evident that fluid shear stress stimulates Na/H exchanger isoform 3 (NHE3) exocytosis and trafficking to the apical membrane of the proximal tubule cells. Second, experimental data and modeling calculations provide strong evidence that brush border microvilli function as flow sensors in the proximal tubule. Flow-induced changes of proximal tubule absorption depend on the changes of torque (bending moment) on the microvilli, and that an intact actin cytoskeleton is required to transduce signals from the brush border to cell and alter transport activity, NHE3 expression and trafficking. Third, the increased NHE3 exocytosis by dopamine blockers enhanced tubule sensitivity to torque, and the IP receptor-mediated intracellular Ca signaling is a critical step in transduction of fluid drag on microvillus drag tips in modulating Na and HCO transport. Finally, in all of our experimental studies, flow-dependent transport in mouse tubules was achieved with virtually no change in tubule cell volume. Our model calculations suggest that this observation is strong evidence for proportional luminal and peritubular effects of flow on transporter density.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519745PMC
January 2016

Imaging and analysis of microcalcifications and lipid/necrotic core calcification in fibrous cap atheroma.

Int J Cardiovasc Imaging 2015 Jun 3;31(5):1079-87. Epub 2015 Apr 3.

Department of Biomedical Engineering, The City College New York, The City University of New York, Steinman Hall T-401, 140th Street and Convent Ave, New York, NY, 10031, USA.

The presence of microcalcifications (µCalcs) >5 µm within the cap of human fibroatheroma has been shown to produce a 200-700% increase in peak circumferential stress, which can transform a stable plaque into a vulnerable one, whereas µCalcs < 5 µm do not appear to increase risk. We quantitatively examine the possibility to distinguish caps with µCalcs > 5 µm based on the gross morphological features of fibroatheromas, and the correlation between the size and distribution of µCalcs in the cap and the calcification in the lipid/necrotic core beneath it. Atherosclerotic lesions (N = 72) were imaged using HR-μCT at 2.1-μm resolution for detailed analysis of atheroma morphology and composition, and validated using non-decalcified histology. At 2.1-μm resolution one observes four different patterns of calcification within the lipid/necrotic core, and is able to elucidate the 3D spatial progression of the calcification process using these four patterns. Of the gross morphological features identified, only minimum cap thickness positively correlated with the existence of µCalcs > 5 µm in the cap. We also show that µCalcs in the cap accumulate in the vicinity of the lipid/necrotic core boundary with few on the lumen side of the cap. HR-μCT enables three-dimensional assessment of soft tissue composition, lipid content, calcification patterns within lipid/necrotic cores and analysis of the axial progression of calcification within individual atheroma. The distribution of µCalcs within the cap is highly non-uniform and decreases sharply as one proceeds from the lipid pool/necrotic core boundary to the lumen.
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http://dx.doi.org/10.1007/s10554-015-0650-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5253073PMC
June 2015

Regulation of glomerulotubular balance. III. Implication of cytosolic calcium in flow-dependent proximal tubule transport.

Am J Physiol Renal Physiol 2015 Apr 28;308(8):F839-47. Epub 2015 Jan 28.

Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut;

In the proximal tubule, axial flow (drag on brush-border microvilli) stimulates Na(+) and HCO3 (-) reabsorption by modulating both Na/H exchanger 3 (NHE3) and H-ATPase activity, a process critical to glomerulotubular balance. We have also demonstrated that blocking the angiotensin II receptor decreases baseline transport, but preserves the flow effect; dopamine leaves baseline fluxes intact, but abrogates the flow effect. In the current work, we provide evidence implicating cytosolic calcium in flow-dependent transport. Mouse proximal tubules were microperfused in vitro at perfusion rates of 5 and 20 nl/min, and reabsorption of fluid (Jv) and HCO3 (-) (JHCO3) were measured. We examined the effect of high luminal Ca(2+) (5 mM), 0 mM Ca(2+), the Ca(2+) chelator BAPTA-AM, the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate (2-APB), and the Ca-ATPase inhibitor thapsigargin. In control tubules, increasing perfusion rate from 5 to 20 nl/min increased Jv by 62% and JHCO3 by 104%. With respect to Na(+) reabsorption, high luminal Ca(2+) decreased transport at low flow, but preserved the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect; thapsigargin decreased baseline flow, leaving the flow effect intact. With respect to HCO3 (-) reabsorption, high luminal Ca(2+) decreased transport at low flow and mildly diminished the flow-induced increase; low luminal Ca(2+) had little impact; both BAPTA and 2-APB had no effect on baseline flux, but abrogated the flow effect. These data implicate IP3 receptor-mediated intracellular Ca(2+) signaling as a critical step in transduction of microvillous drag to modulate Na(+) and HCO3 (-) transport.
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http://dx.doi.org/10.1152/ajprenal.00601.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398834PMC
April 2015

Effect of tissue properties, shape and orientation of microcalcifications on vulnerable cap stability using different hyperelastic constitutive models.

J Biomech 2014 Mar 13;47(4):870-7. Epub 2014 Jan 13.

Department of Biomedical Engineering, The City College of The City University of New York, New York, USA; The Graduate Center of The City University of New York, New York, NY, USA. Electronic address:

Approximately half of all cardiovascular deaths associated with acute coronary syndrome occur when the thin fibrous cap tissue overlying the necrotic core in a coronary vessel is torn, ripped or fissured under the action of high blood pressure. From a biomechanics point of view, the rupture of an atheroma is due to increased mechanical stresses in the lesion, in which the ultimate stress (i.e. peak circumferential stress (PCS) at failure) of the tissue is exceeded. Several factors including the cap thickness, morphology, residual stresses and tissue composition of the atheroma have been shown to affect the PCS. Also important, we recently demonstrated that microcalcifications (μCalcs>5 µm are a common feature in human atheroma caps, which behave as local stress concentrators, increasing the local tissue stress by at least a factor of two surpassing the ultimate stress threshold for cap tissue rupture. In the present study, we used both idealized µCalcs with spherical shape and actual µCalcs from human coronary atherosclerotic caps, to determine their effect on increasing the circumferential stress in the fibroatheroma cap using different hyperelastic constitutive models. We have found that the stress concentration factor (SCF) produced by μCalcs in the fibroatheroma cap is affected by the material tissue properties, μCalcs spacing, aspect ratio and their alignment relative to the tensile axis of the cap.
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http://dx.doi.org/10.1016/j.jbiomech.2014.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019736PMC
March 2014

Mechanosensory responses of osteocytes to physiological forces occur along processes and not cell body and require αVβ3 integrin.

Proc Natl Acad Sci U S A 2013 Dec 9;110(52):21012-7. Epub 2013 Dec 9.

Departments of Orthopaedic Surgery, Neuroscience, and Urology, and Laboratories of Musculoskeletal Orthopaedic Research at Einstein-Montefiore, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY 10461.

Osteocytes in the lacunar-canalicular system of the bone are thought to be the cells that sense mechanical loading and transduce mechanical strain into biomechanical responses. The goal of this study was to evaluate the extent to which focal mechanical stimulation of osteocyte cell body and process led to activation of the cells, and determine whether integrin attachments play a role in osteocyte activation. We use a novel Stokesian fluid stimulus probe to hydrodynamically load osteocyte processes vs. cell bodies in murine long bone osteocyte Y4 (MLO-Y4) cells with physiological-level forces <10 pN without probe contact, and measured intracellular Ca(2+) responses. Our results indicate that osteocyte processes are extremely responsive to piconewton-level mechanical loading, whereas the osteocyte cell body and processes with no local attachment sites are not. Ca(2+) signals generated at stimulated sites spread within the processes with average velocity of 5.6 μm/s. Using the near-infrared fluorescence probe IntegriSense 750, we demonstrated that inhibition of αVβ3 integrin attachment sites compromises the response to probe stimulation. Moreover, using apyrase, an extracellular ATP scavenger, we showed that Ca(2+) signaling from the osteocyte process to the cell body was greatly diminished, and thus dependent on ATP-mediated autocrine signaling. These findings are consistent with the hypothesis that osteocytes in situ are highly polarized cells, where mechanotransduction occurs at substrate attachment sites along the processes at force levels predicted to occur at integrin attachment sites in vivo. We also demonstrate the essential role of αVβ3 integrin in osteocyte-polarized mechanosensing and mechanotransduction.
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http://dx.doi.org/10.1073/pnas.1321210110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3876252PMC
December 2013

Changing views of the biomechanics of vulnerable plaque rupture: a review.

Ann Biomed Eng 2014 Feb 11;42(2):415-31. Epub 2013 Jul 11.

Department of Biomedical Engineering, The City College of New York, Steinman Hall, 160 Convent Ave, New York, NY, 10031, USA.

This review examines changing perspectives on the biomechanics of vulnerable plaque rupture over the past 25 years from the first finite element analyses (FEA) showing that the presence of a lipid pool significantly increases the local tissue stress in the atheroma cap to the latest imaging and 3D FEA studies revealing numerous microcalcifications in the cap proper and a new paradigm for cap rupture. The first part of the review summarizes studies describing the role of the fibrous cap thickness, tissue properties, and lesion geometry as main determinants of the risk of rupture. Advantages and limitations of current imaging technologies for assessment of vulnerable plaques are also discussed. However, the basic paradoxes as to why ruptures frequently did not coincide with location of PCS and why caps >65 μm thickness could rupture at tissue stresses significantly below the 300 kPa critical threshold still remained unresolved. The second part of the review describes recent studies in the role of microcalcifications, their origin, shape, and clustering in explaining these unresolved issues including the actual mechanism of rupture due to the explosive growth of tiny voids (cavitation) in local regions of high stress concentration between closely spaced microinclusions oriented along their tensile axis.
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http://dx.doi.org/10.1007/s10439-013-0855-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888649PMC
February 2014

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process.

Proc Natl Acad Sci U S A 2013 Jul 1;110(29):12096-101. Epub 2013 Jul 1.

Department of Biomedical Engineering, City College of New York, New York, NY 10031, USA.

Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid-flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotide-degrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network.
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http://dx.doi.org/10.1073/pnas.1310003110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3718158PMC
July 2013

Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries.

Proc Natl Acad Sci U S A 2013 Jun 3;110(26):10741-6. Epub 2013 Jun 3.

Department of Biomedical Engineering, City College of New York, New York, NY 10031, USA.

Using 2.1-µm high-resolution microcomputed tomography, we have examined the spatial distribution, clustering, and shape of nearly 35,000 microcalcifications (µCalcs) ≥ 5 µm in the fibrous caps of 22 nonruptured human atherosclerotic plaques. The vast majority of these µCalcs were <15 µm and invisible at the previously used 6.7-µm resolution. A greatly simplified 3D finite element analysis has made it possible to quickly analyze which of these thousands of minute inclusions are potentially dangerous. We show that the enhancement of the local tissue stress caused by particle clustering increases rapidly for gap between particle pairs (h)/particle diameter (D) < 0.4 if particles are oriented along the tensile axis of the cap. Of the thousands of µCalcs observed, there were 193 particle pairs with h/D ≤ 2 (tissue stress factor > 2), but only 3 of these pairs had h/D ≤ 0.4, where the local tissue stress could increase a factor > 5. Using nondecalcified histology, we also show that nearly all caps have µCalcs between 0.5 and 5 µm and that the µCalcs ≥ 5 µm observed in high-resolution microcomputed tomography are agglomerations of smaller calcified matrix vesicles. µCalcs < 5 µm are predicted to be not harmful, because the tiny voids associated with these very small particles will not explosively grow under tensile forces because of their large surface energy. These observations strongly support the hypothesis that nearly all fibrous caps have µCalcs, but only a small subset has the potential for rupture.
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http://dx.doi.org/10.1073/pnas.1308814110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696743PMC
June 2013

The explosive growth of small voids in vulnerable cap rupture; cavitation and interfacial debonding.

J Biomech 2013 Jan 6;46(2):396-401. Epub 2012 Dec 6.

Department of Biomedical Engineering, The City College of New York of The City University of New York, NY, USA.

While it is generally accepted that ruptures in fibrous cap atheromas cause most acute coronary deaths, and that plaque rupture occurs in the fibrous cap at the location where the tissue stress exceeds a certain critical peak circumferential stress, the exact mechanism of rupture initiation remains unclear. We recently reported the presence of multiple microcalcifications (μCalcs) <50 μm diameter embedded within the fibrous cap, μCalcs that could greatly increase cap instability by introducing up to a 5-fold increase in local tissue stress. Here, we explore the hypothesis that, aside from cap thickness, μCalc size and interparticle spacing are principal determinants of cap rupture risk. Also, we propose that cap rupture is initiated near the poles of the μCalcs due to the presence of tiny voids that explosively grow at a critical tissue stress and then propagate across the fibrous cap. We develop a theoretical model based on classic studies in polymeric materials by Gent (1980), which indicates that cavitation as opposed to interfacial debonding is the more likely mechanism for cap rupture produced by μCalcs <65 μm diameter. This analysis suggests that there is a critical μCalc size range, from 5 μm to 65 μm, in which cavitation should be prevalent. This hypothesis for cap rupture is strongly supported by our latest high resolution μCT studies in which we have observed trapped voids in the vicinity of μCalcs within fibrous caps in human coronaries.
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http://dx.doi.org/10.1016/j.jbiomech.2012.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019735PMC
January 2013

Mechanosensation and transduction in osteocytes.

Bone 2013 Jun 18;54(2):182-90. Epub 2012 Oct 18.

Department of Oral Cell Biology, ACTA-VU University Amsterdam, Research Institute MOVE, Gustav Mahlerlaan 3004, 1081 LA Amsterdam, The Netherlands.

The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes.
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http://dx.doi.org/10.1016/j.bone.2012.10.013DOI Listing
June 2013

Regulation of glomerulotubular balance: II: impact of angiotensin II on flow-dependent transport.

Am J Physiol Renal Physiol 2012 Dec 5;303(11):F1507-16. Epub 2012 Sep 5.

Dept. of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520-8026, USA.

Underlying glomerulotubular balance (GTB) is the impact of axial flow to regulate Na(+) and HCO(3)(-) transport by modulating Na(+)-H(+) exchanger 3 (NHE3) and H-ATPase activity. It is not known whether the cascade of events following a change in flow relies on local angiotensin (ANG II) generation or receptor availability. Mouse tubules were microperfused in vitro at flows of 5 and 20 nl/min, and net fluid (J(v)) and HCO(3)(-) (J(HCO3)) absorption and cell height were measured. Na(+) (J(Na)) and Cl(-) (J(Cl)) absorption and changes in microvillous torque were estimated. Raising flow increased Na(+) and HCO(3)(-) reabsorption but did not change either Cl(-) transport or cell volume. Losartan reduced absolute Na(+) and HCO(3)(-) absorption at both low and high flows but did not affect fractional flow-stimulated transport. Compared with controls, in AT(1a) knockout (KO) mouse tubules, 53% of flow-stimulated Na(+) absorption was abolished, but flow-stimulated HCO(3)(-) absorption was retained at similar levels. The remaining flow-stimulated J(HCO3) was eliminated by the H-ATPase inhibitor bafilomycin. Inhibition of the AT(2) receptor by PD123319 increased both J(Na) and J(HCO3) but did not affect flow-mediated fractional changes. NHE3 expression at the protein level was reduced in AT(1a) KO mice kidneys. We conclude that 1) although the AT(1a) receptor is necessary for flow to impact NHE3, the effect on H(+)-ATPase is independent of AT(1a); 2) the small flow-mediated changes in cell volume suggest a coordinate flow effect on both luminal and basolateral transporters; and 3) there is no evidence of flow-dependent Cl(-) transport, and thus no evidence for convective paracellular Cl(-) transport in mouse tubules.
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http://dx.doi.org/10.1152/ajprenal.00277.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532483PMC
December 2012

A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: potential implications for plaque rupture.

Am J Physiol Heart Circ Physiol 2012 Sep 9;303(5):H619-28. Epub 2012 Jul 9.

Department of Biomedical Engineering, The City College of New York, The City University of New York, New York, New York 10031, USA.

The role of microcalcifications (μCalcs) in the biomechanics of vulnerable plaque rupture is examined. Our laboratory previously proposed (Ref. 44), using a very limited tissue sample, that μCalcs embedded in the fibrous cap proper could significantly increase cap instability. This study has been greatly expanded. Ninety-two human coronary arteries containing 62 fibroatheroma were examined using high-resolution microcomputed tomography at 6.7-μm resolution and undecalcified histology with special emphasis on calcified particles <50 μm in diameter. Our results reveal the presence of thousands of μCalcs, the vast majority in lipid pools where they are not dangerous. However, 81 μCalcs were also observed in the fibrous caps of nine of the fibroatheroma. All 81 of these μCalcs were analyzed using three-dimensional finite-element analysis, and the results were used to develop important new clinical criteria for cap stability. These criteria include variation of the Young's modulus of the μCalc and surrounding tissue, μCalc size, and clustering. We found that local tissue stress could be increased fivefold when μCalcs were closely spaced, and the peak circumferential stress in the thinnest nonruptured cap (66 μm) if no μCalcs were present was only 107 kPa, far less than the proposed minimum rupture threshold of 300 kPa. These results and histology suggest that there are numerous μCalcs < 15 μm in the caps, not visible at 6.7-μm resolution, and that our failure to find any nonruptured caps between 30 and 66 μm is a strong indication that many of these caps contained μCalcs.
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http://dx.doi.org/10.1152/ajpheart.00036.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468470PMC
September 2012

Quantitative model for predicting lymph formation and muscle compressibility in skeletal muscle during contraction and stretch.

Proc Natl Acad Sci U S A 2012 Jun 21;109(23):9185-90. Epub 2012 May 21.

Department of Biomedical Engineering, The City College of New York, New York, NY 10031, USA.

Skeletal muscle is widely perceived as nearly incompressible despite the fact that blood and lymphatic vessels within the endomysial and perimysial spaces undergo significant changes in diameter and length during stretch and contraction. These fluid shifts between fascicle and interstitial compartments have proved extremely difficult to measure. In this paper, we propose a theoretical framework based on a space-filling hexagonal fascicle array to provide predictions of the displacement of blood and lymph into and out of the muscle's endomysium and perimysium during stretch and contraction. We also use this model to quantify the distribution of blood and initial lymphatic (IL) vessels within a fascicle and its perimysial space using data for the rat spinotrapezius muscle. On average, there are 11 muscle fibers, 0.4 arteriole/venule pairs, and 0.2 IL vessels per fascicle. The model predicts that the blood volume in the endomysial space increases 24% and decreases 22% for a 20% contraction and stretch, respectively. However, these significant changes in blood volume in the endomysium produce a change of only ∼2% in fascicle cross-sectional area. In contrast, the entire muscle deviates from isovolumetry by 7% and 6% for a 20% contraction and stretch, respectively, largely attributable to the significantly larger blood volume changes that occur in the perimysial space. This suggests that arcade blood vessels in the perimysial space provide the primary pumping action required for the filling and emptying of ILs during muscular contraction and stretch.
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http://dx.doi.org/10.1073/pnas.1206398109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384164PMC
June 2012

Regulation of glomerulotubular balance. I. Impact of dopamine on flow-dependent transport.

Am J Physiol Renal Physiol 2012 Aug 2;303(3):F386-95. Epub 2012 May 2.

Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520-8026, USA.

In response to volume expansion, locally generated dopamine decreases proximal tubule reabsorption by reducing both Na/H-exchanger 3 (NHE3) and Na-K-ATPase activity. We have previously demonstrated that mouse proximal tubules in vitro respond to changes in luminal flow with proportional changes in Na(+) and HCO(3)(-) reabsorption and have suggested that this observation underlies glomerulotubular balance. In the present work, we investigate the impact of dopamine on the sensitivity of reabsorptive fluxes to changes in luminal flow. Mouse proximal tubules were microperfused in vitro at low and high flow rates, and volume and HCO(3)(-) reabsorption (J(v) and J(HCO3)) were measured, while Na(+) and Cl(-) reabsorption (J(Na) and J(Cl)) were estimated. Raising luminal flow increased J(v), J(Na), and J(HCO3) but did not change J(Cl). Luminal dopamine did not change J(v), J(Na), and J(HCO3) at low flow rates but completely abolished the increments of Na(+) absorption by flow and partially inhibited the flow-stimulated HCO(3)(-) absorption. The remaining flow-stimulated HCO(3)(-) absorption was completely abolished by bafilomycin. The DA1 receptor blocker SCH23390 and the PKA inhibitor H89 blocked the effect of exogenous dopamine and produced a two to threefold increase in the sensitivity of proximal Na(+) reabsorption to luminal flow rate. Under the variety of perfusion conditions, changes in cell volume were small and did not always parallel changes in Na(+) transport. We conclude that 1) dopamine inhibits flow-stimulated NHE3 activity by activation of the DA1 receptor via a PKA-mediated mechanism; 2) dopamine has no effect on flow-stimulated H-ATPase activity; 3) there is no evidence of flow stimulation of Cl(-) reabsorption; and 4) the impact of dopamine is a coordinated modulation of both luminal and peritubular Na(+) transporters.
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http://dx.doi.org/10.1152/ajprenal.00531.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433864PMC
August 2012

An Integrative Review of Mechanotransduction in Endothelial, Epithelial (Renal) and Dendritic Cells (Osteocytes).

Cell Mol Bioeng 2011 Dec;4(4):510-537

Department of Biomedical Engineering, The City College of the City University of New York, New York, NY 10031, USA.

In this review we will examine from a biomechanical and ultrastructural viewpoint how the cytoskeletal specialization of three basic cell types, endothelial cells (ECs), epithelial cells (renal tubule) and dendritic cells (osteocytes), enables the mechano-sensing of fluid flow in both their native environment and in culture, and the downstream signaling that is initiated at the molecular level in response to fluid flow. These cellular responses will be discussed in terms of basic mysteries and paradoxes encountered by each cell type. In ECs fluid shear stress (FSS) is nearly entirely attenuated by the endothelial glycocalyx that covers their apical membrane and yet FSS is communicated to both intracellular and junctional molecular components in activating a wide variety of signaling pathways. The same is true in proximal tubule (PT) cells where a dense brush border of microvilli covers the apical surface and the flow at the apical membrane is negligible. A four decade old unexplained mystery is the ability of PT epithelia to reliably reabsorb 60% of the flow entering the tubule regardless of the glomerular filtration rate. In the cortical collecting duct (CCD) the flow rates are so low that a special sensing apparatus, a primary cilia is needed to detect very small variations in tubular flow. In bone it has been a century old mystery as to how osteocytes embedded in a stiff mineralized tissue are able to sense miniscule whole tissue strains that are far smaller than the cellular level strains required to activate osteocytes .
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http://dx.doi.org/10.1007/s12195-011-0179-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748935PMC
December 2011

On the electrophysiological response of bone cells using a Stokesian fluid stimulus probe for delivery of quantifiable localized picoNewton level forces.

J Biomech 2011 Jun 20;44(9):1702-8. Epub 2011 Apr 20.

Department of Biomedical Engineering, The City College of New York, Steinman Hall, Room T-404B, Convent Avenue and 140th Street, New York, NY 10031, USA.

A Stokesian fluid stimulus probe (SFSP), capable of delivering quantifiable pN level hydrodynamic forces, is developed to distinguish the electrophysiological response of the cell process and cell body of osteocyte-like MLO-Y4 cells without touching the cell or its substrate. The hydrodynamic disturbance is a short lived (100 ms), constant strength pressure pulse that propagates nearly instantaneously through the medium creating a nearly spherical expanding fluid bolus surrounding a 0.8 μm micropipette tip. Laboratory model experiments show that the growth of the bolus and the pressure field can be closely modeled by quasi-steady Stokes flow through a circular orifice provided the tip Reynolds number, Re(t)<0.03. By measuring the deflection of the dendritic processes between discrete attachment sites, and applying a detailed ultrastructural model for the central actin filament bundle within the process, one is able to calculate the forces produced by the probe using elastic beam theory. One finds that forces between 1 and 2.3 pN are sufficient to initiate electrical signaling when applied to the cell process, but not the much softer cell body. Even more significantly, cellular excitation by the process only occurs when the probe is directed at discrete focal attachment sites along the cell process. This suggests that electrical signaling is initiated at discrete focal attachments along the cell process and that these sites are likely integrin-mediated complexes associated with stretch-activated ion channels though their molecular structure is unknown.
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http://dx.doi.org/10.1016/j.jbiomech.2011.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427000PMC
June 2011

Shear stress-induced changes of membrane transporter localization and expression in mouse proximal tubule cells.

Proc Natl Acad Sci U S A 2010 Dec 24;107(50):21860-5. Epub 2010 Nov 24.

Department of Cellular and Molecular Physiology, School of Medicine, Yale University, New Haven, CT 06520, USA.

Our previous studies of microperfused single proximal tubule showed that flow-dependent Na(+) and HCO(3)(-) reabsorption is due to a modulation of both NHE3 and vacuolar H(+)-ATPase (V-ATPase) activity. An intact actin cytoskeleton was indicated to provide a structural framework for proximal tubule cells to transmit mechanical forces and subsequently modulate cellular functions. In this study, we have used mouse proximal tubule (MPT) cells as a model to study the role of fluid shear stress (FSS) on apical NHE3 and V-ATPase and basolateral Na/K-ATPase trafficking and expression. Our hypothesis is that FSS stimulates both apical and basolateral transporter expression and trafficking, which subsequently mediates salt and volume reabsorption. We exposed MPT cells to 0.2 dynes/cm(2) FSS for 3 h and performed confocal microscopy and Western blot analysis to compare the localization and expression of both apical and basolateral transporters in control cells and cells subjected to FSS. Our findings show that FSS leads to an increment in the amount of protein expression, and a translocation of apical NHE3 and V-ATPase from the intracellular compartment to the apical plasma membrane and Na/K-ATPase to the basolateral membrane. Disrupting actin by cytochalasin D blocks the FSS-induced changes in NHE3 and Na/K-ATPase, but not V-ATPase. In contrast, FSS-induced V-ATPase redistribution and expression are largely inhibited by colchicine, an agent that blocks microtubule polymerization. Our findings suggest that the actin cytoskeleton plays an important role in FSS-induced NHE3 and Na/K-ATPase trafficking, and an intact microtubule network is critical in FSS-induced modulation of V-ATPase in proximal tubule cells.
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http://dx.doi.org/10.1073/pnas.1015751107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3003103PMC
December 2010

Mechanotransduction in the renal tubule.

Am J Physiol Renal Physiol 2010 Dec 1;299(6):F1220-36. Epub 2010 Sep 1.

Dept. of Biomedical Engineering, The City College of New York, New York, NY 10031, USA.

The role of mechanical forces in the regulation of glomerulotubular balance in the proximal tubule (PT) and Ca(2+) signaling in the distal nephron was first recognized a decade ago, when it was proposed that the microvilli in the PT and the primary cilium in the cortical collecting duct (CCD) acted as sensors of local tubular flow. In this review, we present a summary of the theoretical models and experiments that have been conducted to elucidate the structure and function of these unique apical structures in the modulation of Na(+), HCO(3)(-), and water reabsorption in the PT and Ca(2+) signaling in the CCD. We also contrast the mechanotransduction mechanisms in renal epithelium with those in other cells in which fluid shear stresses have been recognized to play a key role in initiating intracellular signaling, most notably endothelial cells, hair cells in the inner ear, and bone cells. In each case, small hydrodynamic forces need to be greatly amplified before they can be sensed by the cell's intracellular cytoskeleton to enable the cell to regulate its membrane transporters or stretch-activated ion channels in maintaining homeostasis in response to changing flow conditions.
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http://dx.doi.org/10.1152/ajprenal.00453.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006307PMC
December 2010

Computational stress analysis of atherosclerotic plaques in ApoE knockout mice.

Ann Biomed Eng 2010 Mar;38(3):738-47

Department of Biomedical Engineering, The City College of New York, CUNY, New York, NY 10031, USA.

The aortic sinus lesions of apolipoprotein E knockout (ApoE KO) mice seldom show any signs of fibrous cap disruption, whereas cap ruptures have been recently reported in the proximal part of their brachiocephalic arteries (BCA). We use histology based finite element analysis to evaluate peak circumferential stresses in aortic and BCA lesions from six 42-56 week-old fat-fed ApoE KO mice. This analysis is able to both explain the greater stability of aortic lesions in mice and provide new insight into the BCA lesion as a model for the stability of human lesions with and without microcalcifications in their fibrous caps. The predicted average peak stress in fibrous caps of aortic lesions of 205.8 kPa is significantly lower than the average value of maximum stresses of 568.8 kPa in BCA caps. The aortic plaque stresses only slightly depend on the cap thickness, while BCA lesions demonstrate an exponential growth of peak cap stresses with decreasing cap thickness similar to human vulnerable plaques. Murine BCA ruptured lesions with mean cap thickness of 2 microm show stresses approximately 1400 kPa, three times higher than human ruptured plaques with a mean cap thickness of 23 microm without microcalcifications in the cap, but nearly identical to the peak stress around an elongated microcalcification with aspect ratio 2 in a human thin cap approximately 50 microm thick. We predict biomechanical stress patterns in mouse BCA close to human vulnerable plaques without microcalcification in the cap, while aortic lesions show stress tendency similar to stable lesions in human.
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http://dx.doi.org/10.1007/s10439-009-9897-5DOI Listing
March 2010

Fulfilling the dream: the importance of doing what you believe and being taken seriously. BMES Inaugural Diversity Award and Lecture: BMES Annual Meeting, October 10, 2009.

Authors:
Sheldon Weinbaum

Ann Biomed Eng 2010 Mar;38(3):1132-40

Department of Biomedical Engineering, Grove School of Engineering, The City College of New York, New York, NY, USA.

In this Inaugural Diversity Lecture I trace the diversity struggles in my own life over the past 46 years since the historic 1963 "I Have a Dream" speech of Martin Luther King, which has changed this nation forever. After a brief personal history, the paper is divided into three major parts; "My consciousness raising years", "Fulfilling the dream", and NIH Minority Scholars Program. The paper ends with some concluding thoughts on the importance of being taken seriously.
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http://dx.doi.org/10.1007/s10439-009-9893-9DOI Listing
March 2010