The role of anatomic shape features in the prognosis of uncomplicated type B aortic dissection initially treated with optimal medical therapy.

OBJECTIVE: Currently, the long-term outcomes of uncomplicated type B aortic dissection (TBAD) patients managed with optimal medical therapy (OMT) remain poor. Aortic expansion is a major factor that determines patient long-term survival. The objective of this study was to investigate the association between anatomic shape features and (i) OMT outcome; (ii) aortic growth rate for TBAD patients initially treated with OMT. METHODS: 108 CT images of TBAD in the acute and chronic phases were collected from 46 patients who were initially treated with OMT. Statistical shape models (SSM) of TBAD were constructed to extract shape features from the earliest initial CT scans of each patient by using principal component analysis (PCA) and partial least square (PLS) regression. Additionally, conventional shape features (e.g., aortic diameter) were quantified from the earliest CT scans as a baseline for comparison. We identified conventional and SSM features that were significant in separating OMT "success" and failure patients. Moreover, the aortic growth rate was predicted by SSM and conventional features using linear and nonlinear regression with cross-validations. RESULTS: Size-related SSM and conventional features (mean aortic diameter: p=0.0484, centerline length: p=0.0112, PCA score c1: p=0.0192, and PLS scores t1: p=0.0004, t2: p=0.0274) were significantly different between OMT success and failure groups, but these features were incapable of predicting the aortic growth rate. SSM shape features showed superior results in growth rate prediction compared to conventional features. Using multiple linear regression, the conventional, PCA, and PLS shape features resulted in root mean square errors (RMSE) of 1.23, 0.85, and 0.84 mm/year, respectively, in leave-one-out cross-validations. Nonlinear support vector regression (SVR) led to improved RMSE of 0.99, 0.54, and 0.43 mm/year, for the conventional, PCA, and PLS features, respectively. CONCLUSION: Size-related shape features of the earliest scan were correlated with OMT failure but led to large errors in the prediction of the aortic growth rate. SSM features in combination with nonlinear regression could be a promising avenue to predict the aortic growth rate.

A 1D model characterizing the role of spatiotemporal contraction distributions on lymph transport.

Lymphedema is a condition in which lymph transport is compromised. The factors that govern the timing of lymphatic contractions are largely unknown; however, these factors likely play a central role in lymphatic health. Computational models have proven useful in quantifying changes in lymph transport; nevertheless, there is still much unknown regarding the regulation of contractions. The purpose of this paper is to utilize computational modeling to examine the role of pacemaking activity in lymph transport. A 1D fluid-solid modeling framework was utilized to describe the interaction between the contracting vessel and the lymph flow. The distribution of contractions along a three-lymphangion chain in time and space was determined by specifying the pacemaking sites and parameters obtained from experimentation. The model effectively replicates the contractility patterns in experiments. Quantitatively, the flow rates were measured at 5.44 and 2.29 [Formula: see text], and the EF values were 78% and less than 33% in the WT and KO models, respectively, which are consistent with the literature. Applying pacemaking parameters in this modeling framework effectively captures lymphatic contractile wave propagations and their relation to lymph transport. It can serve as a motivation for conducting novel studies to evaluate lymphatic pumping function during the development of lymphedema.

Effect of Aging, Sex, and Gene (Fbln5) on Arterial Stiffness of Mice: 20 Weeks Adult Fbln5-knockout Mice Have Older Arteries than 100 Weeks Wild-Type Mice.

The arterial stiffening is a strong independent predictor of cardiovascular risk and has been used to characterize the biological age of arteries ('arterial age'). Here we revealed that the Fbln5 gene knockout (Fbln5 -/- ) significantly increases the arterial stiffening for both male and female mice. We also showed that the arterial stiffening increases with natural aging, but the stiffening effect of Fbln5 -/- is much more severe than aging. The arterial stiffening of 20 weeks old mice with Fbln5 -/- is much higher than that at 100 weeks in wild-type (Fbln5 +/+ ) mice, which indicates that 20 weeks mice (equivalent to ∼26 years old humans) with Fbln5 -/- have older arteries than 100 weeks wild-type mice (equivalent to ∼77 years humans). Histological microstructure changes of elastic fibers in the arterial tissue elucidate the underlying mechanism of the increase of arterial stiffening due to Fbln5-knockout and aging. These findings provide new insights to reverse 'arterial age' due to abnormal mutations of Fbln5 gene and natural aging. This work is based on a total of 128 biaxial testing samples of mouse arteries and our recently developed unified-fiber-distribution (UFD) model. The UFD model considers the fibers in the arterial tissue as a unified distribution, which is more physically consistent with the real fiber distribution of arterial tissues than the popular fiber-family-based models (e.g., the well-know Gasser-Ogden-Holzapfel [GOH] model) that separate the fiber distribution into several fiber families. Thus, the UFD model achieves better accuracies with less material parameters. To our best knowledge, the UFD model is the only existing accurate model that could capture the property/stiffness differences between different groups of the experimental data discussed here.

Effect of Nonlinear Hyperelastic Property of Arterial Tissues on the Pulse Wave Velocity Based on the Unified-Fiber-Distribution (UFD) Model.

Pulse wave velocity (PWV) is a key, independent risk factor for future cardiovascular events. The Moens-Korteweg equation describes the relation between PWV and the stiffness of arterial tissue with an assumption of isotopic linear elastic property of the arterial wall. However, the arterial tissue exhibits highly nonlinear and anisotropic mechanical behaviors. There is a limited study regarding the effect of arterial nonlinear and anisotropic properties on the PWV. In this study, we investigated the impact of the arterial nonlinear hyperelastic properties on the PWV, based on our recently developed unified-fiber-distribution (UFD) model. The UFD model considers the fibers (embedded in the matrix of the tissue) as a unified distribution, which expects to be more physically consistent with the real fiber distribution than existing models that separate the fiber distribution into two/several fiber families. With the UFD model, we fitted the measured relation between the PWV and blood pressure which obtained a good accuracy. We also modeled the aging effect on the PWV based on observations that the stiffening of arterial tissue increases with aging, and the results agree well with experimental data. In addition, we did parameter studies on the dependence of the PWV on the arterial properties of fiber initial stiffness, fiber distribution, and matrix stiffness. The results indicate the PWV increases with increasing overall fiber component in the circumferential direction. The dependences of the PWV on the fiber initial stiffness, and matrix stiffness are not monotonic and change with different blood pressure. The results of this study could provide new insights into arterial property changes and disease information from the clinical measured PWV data.

A mathematical model of vascular and hemodynamics changes in early and late forms of preeclampsia.

Preeclampsia-eclampsia syndrome is a leading cause of maternal mortality. The precise etiology of preeclampsia is still not well-defined and different forms exist, including early and late forms or preeclampsia, which may arise via distinctly different mechanisms. Low-dose aspirin administered at the end of the first trimester in women identified as high risk has been shown to reduce the incidence of early, but not late, preeclampsia; however, current risk factors show only fair predictive capability. There is a pressing need to develop accurate descriptions for the different forms of preeclampsia. This paper presents 1D fluid, solid, growth, and remodeling models for pregnancies complicated with early and late forms of preeclampsia. Simulations affirm a broad set of literature results that early forms of preeclampsia are characterized by elevated uterine artery pulsatility index (UA-PI) and total peripheral resistance (TPR) and lower cardiac output (CO), with modestly increased mean arterial blood pressure (MAP) in the first half of pregnancy, with elevation of TPR and MAP beginning at 20 weeks. Conversely, late forms of preeclampsia are characterized by only slightly elevated UA-PI and normal pre-term TPR, and slightly elevated MAP and CO throughout pregnancy, with increased TPR and MAP beginning after 34 weeks. Results suggest that preexisting arterial stiffness may be elevated in women that develop both early forms and late forms of preeclampsia; however, data that verify these results are lacking in the literature. Pulse wave velocity increases in early- and late-preeclampsia, coincident with increases in blood pressure; however, these increases are mainly due to the strain-stiffening response of larger arteries, rather than arterial remodeling-derived changes in material properties. These simulations affirm that early forms of preeclampsia may be associated with abnormal placentation, whereas late forms may be more closely associated with preexisting maternal cardiovascular factors; simulations also highlight several critical gaps in available data.

Comparative analysis of arterial compliance in mice genetically null for cathepsins K, L, or S.

Cysteine cathepsins are potent proteases implicated in cardiovascular disease for degrading extracellular matrix (ECM) whose structure and integrity determine the mechanical behavior of arteries. Cathepsin knockout mouse models fed atherogenic diets have been used to study their roles in cardiovascular disease, but the impacts of cathepsin knockout on non-atherosclerotic arterial mechanics are scarce. We examine arterial mechanics in several cathepsin knockout mouse lines (CatK-/-, CatL-/-ApoE-/- and CatS-/-ApoE-/-) and controls (C57/Bl6, apolipoprotein E-/-). Common carotid arteries of three month-old mice were isolated and underwent biaxial mechanical testing and opening angle tests. Measured wall thicknesses and pressure-diameter curves were fed into a 4-fiber constitutive model to assess differences in material properties. Pressure-diameter data revealed CatL-/-ApoE-/- arteries were smaller in caliber compared to CatK-/-, CatS-/-ApoE-/- and ApoE-/- controls and were less compliant than ApoE-/- and CatS-/-ApoE-/- arteries at lower pressures, where elastin governs the mechanical response. CatK-/- arteries showed increased in vivo axial stretches compared to CatL-/-ApoE-/- and CatS-/-ApoE-/- arteries. CatL-/-ApoE-/- arteries were less compliant than ApoE-/- and CatS-/-ApoE-/- arteries pressurized to sub-diastolic pressures. 4-fiber and unified fiber distribution models were able to capture arteries' nonlinear mechanical responses; calculated material parameters suggested that ApoE-/- arteries had increased axial parameters compared to CatL-/-ApoE-/- and CatS-/-ApoE-/- arteries. Taken together, the data suggests that loss of the potent collagenase catK increases axial and circumferential arterial compliance, while knockout of the elastase catL decreased circumferential arterial compliance, and knockout of the elastase catS showed no impact on carotid arterial mechanics.

A mathematical model of maternal vascular growth and remodeling and changes in maternal hemodynamics in uncomplicated pregnancy.

The maternal vasculature undergoes tremendous growth and remodeling (G&R) that enables a > 15-fold increase in blood flow through the uterine vasculature from conception to term. Hemodynamic metrics (e.g., uterine artery pulsatility index, UA-PI) are useful for the prognosis of pregnancy complications; however, improved characterization of the maternal hemodynamics is necessary to improve prognosis. The goal of this paper is to develop a mathematical framework to characterize maternal vascular G&R and hemodynamics in uncomplicated human pregnancies. A validated 1D model of the human vascular tree from the literature was adapted and inlet blood flow waveforms at the ascending aorta at 4 week increments from 0 to 40 weeks of gestation were prescribed. Peripheral resistances of each terminal vessel were adjusted to achieve target flow rates and mean arterial pressure at each gestational age. Vessel growth was governed by wall shear stress (and axial lengthening in uterine vessels), and changes in vessel distensibility were related to vessel growth. Uterine artery velocity waveforms generated from this model closely resembled ultrasound results from the literature. The literature UA-PI values changed significantly across gestation, increasing in the first month of gestation, then dramatically decreasing from 4 to 20 weeks. Our results captured well the time-course of vessel geometry, material properties, and UA-PI. This 1D fluid-G&R model captured the salient hemodynamic features across a broad range of clinical reports and across gestation for uncomplicated human pregnancy. While results capture available data well, this study highlights significant gaps in available data required to better understand vascular remodeling in pregnancy.

A novel computational growth framework for biological tissues: Application to growth of aortic root aneurysm repaired by the V-shape surgery.

Ascending aortic aneurysms (AsAA) often include the dilatation of sinotubular junction (STJ) and extend proximally into the aortic root, which usually leads to aortic insufficiency. The novel surgery of the V-shape resection of the noncoronary sinus, for treatment of AsAA with root ectasia, has been shown to be a simpler procedure compared to traditional surgeries. Our previous study showed that the repaired aortic root aneurysms grew after the surgery. In this study, we developed a novel computational growth framework to model the growth of the aortic root repaired by the V-shape surgery. Specifically, the unified-fiber-distribution (UFD) model was applied to describe the hyperelastic deformation of the aortic tissue. A novel kinematic growth evolution law was proposed based on existing observations that the growth rate is linearly dependent on the wall stress. Moreover, we also obtained patient-specific geometries of the repaired aortic root post-surgery at two follow-up time points (Post-1 and Post-2) for 5 patients, based on clinical CT images. The novel computational growth framework was implemented into the Abaqus UMAT user subroutine and applied to model the growth of the aortic root from Post-1 to Post-2. Patient-specific growth parameters were obtained by an optimization procedure. The predicted geometry and stress of the aortic root at Post-2 agree well with the in vivo results. The novel computational growth framework and the optimized growth parameters could be applied to predict the growth of repaired aortic root aneurysms for new patients and to optimize repair strategies for AsAA.

Characterization of rat tail lymphatic contractility and biomechanics: incorporating nitric oxide-mediated vasoregulation.

The lymphatic system transports lymph from the interstitial space back to the great veins via a series of orchestrated contractions of chains of lymphangions. Biomechanical models of lymph transport, validated with ex vivo or in vivo experimental results, have proved useful in revealing novel insight into lymphatic pumping; however, a need remains to characterize the contributions of vasoregulatory compounds in these modelling tools. Nitric oxide (NO) is a key mediator of lymphatic pumping. We quantified the active contractile and passive biaxial biomechanical response of rat tail collecting lymphatics and changes in the contractile response to the exogenous NO administration and integrated these findings into a biomechanical model. The passive mechanical response was characterized with a three-fibre family model. Nonlinear regression and non-parametric bootstrapping were used to identify best-fit material parameters to passive cylindrical biaxial mechanical data, assessing uniqueness and parameter confidence intervals; this model yielded a good fit (R2 = 0.90). Exogenous delivery of NO via sodium nitroprusside (SNP) elicited a dose-dependent suppression of contractions; the amplitude of contractions decreased by 30% and the contraction frequency decreased by 70%. Contractile function was characterized with a modified Rachev-Hayashi model, introducing a parameter that is related to SNP concentration; the model provided a good fit (R2 = 0.89) to changes in contractile responses to varying concentrations of SNP. These results demonstrated the significant role of NO in lymphatic pumping and provide a predictive biomechanical model to integrate the combined effect of mechanical loading and NO on lymphatic contractility and mechanical response.

Axial stretch regulates rat tail collecting lymphatic vessel contractions.

Lymphatic contractions play a fundamental role in maintaining tissue and organ homeostasis. The lymphatic system relies on orchestrated contraction of collecting lymphatic vessels, via lymphatic muscle cells and one-way valves, to transport lymph from the interstitial space back to the great veins, against an adverse pressure gradient. Circumferential stretch is known to regulate contractile function in collecting lymphatic vessels; however, less is known about the role of axial stretch in regulating contraction. It is likely that collecting lymphatic vessels are under axial strain in vivo and that the opening and closing of lymphatic valves leads to significant changes in axial strain throughout the pumping cycle. The purpose of this paper is to quantify the responsiveness of lympatic pumping to altered axial stretch. In situ measurements suggest that rat tail collecting lymphatic vessels are under an axial stretch of ~1.24 under normal physiological loads. Ex vivo experiments on isolated rat tail collecting lymphatics showed that the contractile metrics such as contractile amplitude, frequency, ejection fraction, and fractional pump flow are sensitive to axial stretch. Multiphoton microscopy showed that the predominant orientation of collagen fibers is in the axial direction, while lymphatic muscle cell nuclei and actin fibers are oriented in both circumferential and longitudinal directions, suggesting an axial component to contraction. Taken together, these results demonstrate the significance of axial stretch in lymphatic contractile function, suggest that axial stretch may play an important role in regulating lymph transport, and demonstrate that changes in axial strains could be an important factor in disease progression.

Sickle Cell Anemia Mediates Carotid Artery Expansive Remodeling That Can Be Prevented by Inhibition of JNK (c-Jun N-Terminal Kinase).

OBJECTIVE: Sickle cell anemia (SCA) causes chronic inflammation and multiorgan damage. Less understood are the arterial complications, most evident by increased strokes among children. Proteolytic mechanisms, biomechanical consequences, and pharmaceutical inhibitory strategies were studied in a mouse model to provide a platform for mechanistic and intervention studies of large artery damage due to sickle cell disease. Approach and Results: Townes humanized transgenic mouse model of SCA was used to test the hypothesis that elastic lamina and structural damage in carotid arteries increased with age and was accelerated in mice homozygous for SCA (sickle cell anemia homozygous genotype [SS]) due to inflammatory signaling pathways activating proteolytic enzymes. Elastic lamina fragmentation observed by 1 month in SS mice compared with heterozygous littermate controls (sickle cell trait heterozygous genotype [AS]). Positive immunostaining for cathepsin K, a powerful collagenase and elastase, confirmed accelerated proteolytic activity in SS carotids. Larger cross-sectional areas were quantified by magnetic resonance angiography and increased arterial compliance in SS carotids were also measured. Inhibiting JNK (c-jun N-terminal kinase) signaling with SP600125 significantly reduced cathepsin K expression, elastin fragmentation, and carotid artery perimeters in SS mice. By 5 months of age, continued medial thinning and collagen degradation was mitigated by treatment of SS mice with JNK inhibitor. CONCLUSIONS: Arterial remodeling due to SCA is mediated by JNK signaling, cathepsin proteolytic upregulation, and degradation of elastin and collagen. Demonstration in Townes mice establishes their utility for mechanistic studies of arterial vasculopathy, related complications, and therapeutic interventions for large artery damage due to SCA.

Lymphatic remodelling in response to lymphatic injury in the hind limbs of sheep.

Contractile activity in the lymphatic vasculature is essential for maintaining fluid balance within organs and tissues. However, the mechanisms by which collecting lymphatics adapt to changes in fluid load and how these adaptations influence lymphatic contractile activity are unknown. Here we report a model of lymphatic injury based on the ligation of one of two parallel lymphatic vessels in the hind limb of sheep and the evaluation of structural and functional changes in the intact, remodelling lymphatic vessel over a 42-day period. We show that the remodelled lymphatic vessel displayed increasing intrinsic contractile frequency, force generation and vessel compliance, as well as decreasing flow-mediated contractile inhibition via the enzyme endothelial nitric oxide synthase. A computational model of a chain of lymphatic contractile segments incorporating these adaptations predicted increases in the flow-generation capacity of the remodelled vessel at the expense of normal mitochondrial function and elevated oxidative stress within the lymphatic muscle. Our findings may inform interventions for mitigating lymphatic muscle fatigue in patients with dysfunctional lymphatics.

Three-dimensional camera anthropometry to assess risk of cephalopelvic disproportion-related obstructed labour in Ethiopia.

Cephalopelvic disproportion (CPD)-related obstructed labour requires delivery via Caesarean section (C/S); however, in low-resource settings around the world, facilities with C/S capabilities are often far away. This paper reports three low-cost tools to assess the risk of CPD, well before labour, to provide adequate time for referral and planning for delivery. We performed tape measurement- and three-dimensional (3D) camera-based anthropometry, using two 3D cameras (Kinect and Structure) on primigravida, gestational age ≥ 36 weeks, from Addis Ababa, Ethiopia. Novel risk scores were developed and tested to identify models with the highest predicted area under the receiver-operator characteristic curve (AUC), detection rate (true positive rate at a 5% false-positive rate, FPR) and triage rate (true negative rate at a 0% false-negative rate). For tape measure, Kinect and Structure, the detection rates were 53%, 61% and 64% (at 5% FPR), the triage rates were 30%, 56% and 63%, and the AUCs were 0.871, 0.908 and 0.918, respectively. Detection rates were 77%, 80% and 84% at the maximum J-statistic, which corresponded to FPRs of 10%, 15% and 11%, respectively, for tape measure, Kinect and Structure. Thus, tape measurement anthropometry was a very good predictor and Kinect and Structure anthropometry were excellent predictors of CPD risk.

Smooth muscle regional contribution to vaginal wall function.

Pelvic organ prolapse is characterized as the descent of the pelvic organs into the vaginal canal. In the USA, there is a 12% lifetime risk for requiring surgical intervention. Although vaginal childbirth is a well-established risk factor for prolapse, the underlying mechanisms are not fully understood. Decreased smooth muscle organization, composition and maximum muscle tone are characteristics of prolapsed vaginal tissue. Maximum muscle tone of the vaginal wall was previously investigated in the circumferential or axial direction under uniaxial loading; however, the vaginal wall is subjected to multiaxial loads. Further, the contribution of vaginal smooth muscle basal (resting) tone to mechanical function remains undetermined. The objectives of this study were to determine the contribution of smooth muscle basal and maximum tone to the regional biaxial mechanical behaviour of the murine vagina. Vaginal tissue from C57BL/6 mice was subjected to extension-inflation protocols (n = 10) with and without basal smooth muscle tone. Maximum tone was induced with KCl under various circumferential (n = 5) and axial (n = 5) loading conditions. The microstructure was visualized with multiphoton microscopy (n = 1), multiaxial histology (n = 4) and multiaxial immunohistochemistry (n = 4). Smooth muscle basal tone decreased material stiffness and increased anisotropy. In addition, maximum vaginal tone was decreased with increasing intraluminal pressures. This study demonstrated that vaginal muscle tone contributed to the biaxial mechanical response of murine vaginal tissue. This may be important in further elucidating the underlying mechanisms of prolapse, in order to improve current preventative and treatment strategies.

A safe, low-cost, easy-to-use 3D camera platform to assess risk of obstructed labor due to cephalopelvic disproportion.

Cephalopelvic disproportion (CPD)-related obstructed labor is accountable for 3-8% of the maternal deaths worldwide. The consequence of CPD-related obstructive labor in the absence of a Caesarian section (C/S) is often maternal or perinatal mortality or morbidity to the mother and/or the infant. Accurate and timely referral of at-risk mothers to health facilities where C/S is a delivery option could reduce maternal mortality in the developing world. The goal of this work was to develop and test the feasibility of a safe, low-cost, easy-to-use, portable tool, using a Microsoft Kinect 3D camera, to identify women at risk for obstructed labor due to CPD. Magnetic resonance imaging (MRI) scans, 3D camera imaging, anthropometry and clinical pelvimetry were collected and analyzed from women 18-40 years of age, at gestational age ≥36+0 weeks with previous C/S due to CPD (n = 43), previous uncomplicated vaginal deliveries (n = 96), and no previous obstetric history (n = 148) from Addis Ababa, Ethiopia. Novel and published CPD risk scores based on anthropometry, clinical pelvimetry, MRI, and Kinect measurements were compared. Significant differences were observed in most anthropometry, clinical pelvimetry, MRI and Kinect measurements between women delivering via CPD-related C/S versus those delivering vaginally. The area under the receiver-operator curve from novel CPD risk scores base on MRI-, Kinect-, and anthropometric-features outperformed novel CPD risk scores based on clinical pelvimetry and previously published indices for CPD risk calculated from these data; e.g., pelvic inlet area, height, and fetal-pelvic index. This work demonstrates the feasibility of a 3D camera-based platform for assessing CPD risk as a novel, safe, scalable approach to better predict risk of CPD in Ethiopia and warrants the need for further blinded, prospective studies to refine and validate the proposed CPD risk scores, which are required before this method can be applied clinically.

The small heat shock protein HSPB1 protects mice from sepsis.

In vitro studies have implicated the small heat shock protein HSPB1 in a range of physiological functions. However, its in vivo relevance is unclear as the phenotype of unstressed HSPB1-/- mice is unremarkable. To determine the impact of HSPB1 in injury, HSPB1-/- and wild type (WT) mice were subjected to cecal ligation and puncture, a model of polymicrobial sepsis. Ten-day mortality was significantly higher in HSPB1-/- mice following the onset of sepsis (65% vs. 35%). Ex vivo mechanical testing revealed that common carotid arteries from HSPB1-/- mice were more compliant than those in WT mice over pressures of 50-120 mm Hg. Septic HSPB1-/- mice also had increased peritoneal levels of IFN-γ and decreased systemic levels of IL-6 and KC. There were no differences in frequency of either splenic CD4+ or CD8+ T cells, nor were there differences in apoptosis in either cell type. However, splenic CD4+ T cells and CD8+ T cells from HSPB1-/- mice produced significantly less TNF and IL-2 following ex vivo stimulation. Systemic and local bacterial burden was similar in HSPB1-/- and WT mice. Thus while HSPB1-/- mice are uncompromised under basal conditions, HSPB1 has a critical function in vivo in sepsis, potentially mediated through alterations in arterial compliance and the immune response.

The relationship between lymphangion chain length and maximum pressure generation established through in vivo imaging and computational modeling.

The intrinsic contraction of collecting lymphatic vessels serves as a pumping system to propel lymph against hydrostatic pressure gradients as it returns interstitial fluid to the venous circulation. In the present study, we proposed and validated that the maximum opposing outflow pressure along a chain of lymphangions at which flow can be achieved increases with the length of chain. Using minimally invasive near-infrared imaging to measure the effective pumping pressure at various locations in the rat tail, we demonstrated increases in pumping pressure along the length of the tail. Computational simulations based on a microstructurally motivated model of a chain of lymphangions informed from biaxial testing of isolated vessels was used to provide insights into the pumping mechanisms responsible for the pressure increases observed in vivo. These models suggest that the number of lymphangions in the chain and smooth muscle cell force generation play a significant role in determining the maximum outflow pressure, whereas the frequency of contraction has no effect. In vivo administration of nitric oxide attenuated lymphatic contraction, subsequently lowering the effective pumping pressure. Computational simulations suggest that the reduction in contractile strength of smooth muscle cells in the presence of nitric oxide can account for the reductions in outflow pressure observed along the lymphangion chain in vivo. Thus, combining modeling with multiple measurements of lymphatic pumping pressure provides a method for approximating intrinsic lymphatic muscle activity noninvasively in vivo while also providing insights into factors that determine the extent that a lymphangion chain can transport fluid against an adverse pressure gradient. NEW & NOTEWORTHY Here, we report the first minimally invasive in vivo measurements of the relationship between lymphangion chain length and lymphatic pumping pressure. We also provide the first in vivo validation of lumped parameter models of lymphangion chains previously developed through data obtained from isolated vessel testing.

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1.

BACKGROUND: Arterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries. METHODS: D-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared with unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow were tested ex vivo to validate critical results from the animal model. RESULTS: D-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified transforming growth factor-ß pathways as having a prominent role in this stiffened arterial response, but this was attributable to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to transforming growth factor-ß. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of transforming growth factor-ß in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild-type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model. CONCLUSIONS: TSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1's activation of the profibrotic signaling pathways of transforming growth factor-ß. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.

Lipid Peroxidation and Altered Antioxidant Profiles with Pediatric HIV Infection and Antiretroviral Therapy in Addis Ababa, Ethiopia.

HIV- and highly active antiretroviral therapy (HAART)-associated elevations in oxidative stress likely play a role in incomplete immune reconstitution, opportunistic infections and non-AIDS co-morbidities. We aimed to test the hypothesis that children living with HIV exhibit elevated markers of oxidative stress and reduced antioxidant profiles and that HAART-therapy will exacerbate these differences. HIV-positive HAART-naïve (n = 50) and HAART-treated (n = 50) and HIV-negative control (n = 50) participants, 3-15 years of age, were recruited from Black Lion Hospital in Ethiopia. Serum malondialdehyde (MDA) and bilirubin were higher and vitamin C and zinc were lower in HAART-naïve and HAART-treated compared with HIV-negative subjects and higher in HAART-treated compared with HAART-naïve subjects. Uric acid was higher in HAART-naïve compared with HAART-treated and HIV-negative subjects. Differences in MDA and several antioxidants were also observed across treatment regimens. Thus, children living with HIV exhibited systemic elevations in oxidative stress and reduction in antioxidants, which are exacerbated with HAART therapy.