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Dive into the research topics where Victoria P. Le is active.

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Featured researches published by Victoria P. Le.


American Journal of Physiology-heart and Circulatory Physiology | 2011

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice

Victoria P. Le; Russell H. Knutsen; Robert P. Mecham; Jessica E. Wagenseil

Increased arterial stiffness and blood pressure are characteristic of humans and adult mice with reduced elastin levels caused by aging or genetic disease. Direct associations have been shown between increased arterial stiffness and hypertension in humans, but it is not known whether changes in mechanical properties or increased blood pressure occur first. Using genetically modified mice with elastin haploinsufficiency (Eln(+/-)), we investigated the temporal relationship between arterial mechanical properties and blood pressure throughout postnatal development. Our results show that some mechanical properties are maintained constant regardless of elastin amounts. The peak diameter compliance for both genotypes occurs near the physiologic pressure at each age, which acts to provide maximum pulse dampening. The stress-strain relationships are similar between genotypes and become nonlinear near the systolic pressure for each age, which serves to limit distension under high pressure. Our results also show that some mechanical properties are affected by reduced elastin levels and that these changes occur before measurable changes in blood pressure. Eln(+/-) mice have decreased aortic diameter and compliance in ex vivo tests that are significant by postnatal day 7 and increased blood pressure that is not significant until postnatal day 14. This temporal relationship suggests that targeting large arteries to increase diameter or compliance may be an effective treatment for human hypertension.


Science Translational Medicine | 2013

Angiotensin-Converting Enzyme–Induced Activation of Local Angiotensin Signaling Is Required for Ascending Aortic Aneurysms in Fibulin-4–Deficient Mice

Jianbin Huang; Yoshito Yamashiro; Christina L. Papke; Yuichi Ikeda; Yanling Lin; Miteshkumar Patel; Tadashi Inagami; Victoria P. Le; Jessica E. Wagenseil; Hiromi Yanagisawa

Up-regulation of angiotensin-converting enzyme in the aortic wall causes aneurysms in fibulin-4–deficient mice, which can be prevented by losartan or captopril. ACEing Aortic Aneurysm Prevention Aortic aneurysms, areas of abnormal dilation of the aorta, can be a fast and unexpected killer, striking unsuspecting patients without previous warning. These aneurysms can occur in patients with atherosclerosis, or even without any known risk factors, but they are particularly common in patients with Marfan syndrome and other types of connective tissue disease. Now, Huang et al. have created a mouse model of genetic predisposition to ascending aortic aneurysms and used it to test potential therapeutic interventions. The mouse model presented by the authors lacks expression of fibulin-4 in vascular smooth muscle cells. Fibulin-4 normally contributes to the structure of elastic fibers and the contractile phenotype of smooth muscle cells in the vasculature. Mutations in the Fbln4 gene have been implicated in human connective tissue disease. The mice lacking vascular fibulin-4 protein predictably developed ascending aortic aneurysms early in life, and their blood vessel walls had a disorganized structure and disrupted elastic fibers. The authors showed that these mice also expressed abnormally high amounts of angiotensin-converting enzyme (ACE) in their ascending aortas, which caused abnormal extracellular signal–regulated kinase signaling through activation of angiotensin receptor 1. When the mutant animals were treated with captopril (an ACE inhibitor) or losartan (an angiotensin receptor blocker), thus interfering with the excess angiotensin signaling early in life, the aortic aneurysms did not develop. This work by Huang and coauthors clarifies a mechanism of aortic aneurysm formation and provides some insight into a potential approach for intervention. Additional work will be needed to determine how much of this mechanism holds true in human patients (and in which subpopulations) and what intervention can help treat aneurysms after they have already formed. Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4SMKO) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms. We report that abnormal up-regulation of angiotensin-converting enzyme (ACE) in SMCs and subsequent activation of angiotensin II (AngII) signaling are involved in the onset of aortic aneurysms in Fbln4SMKO mice. In this model, aneurysm formation was completely prevented by inhibition of the AngII pathway with losartan or captopril within a narrow therapeutic window during the first month of life, even though the altered mechanical properties of blood vessel walls were not reversed by the pharmacological treatment. The therapeutic effects of losartan in Fbln4SMKO mice do not require the AngII receptor type 2 (Agtr2) but likely require both type 1a (Agtr1a) and 1b (Agtr1b) receptors. The results indicate that fibulin-4 is a vascular matrix component required for regulation of local angiotensin signaling and development and maintenance of the SMC phenotype.


Journal of Visualized Experiments | 2012

Mechanical Testing of Mouse Carotid Arteries: from Newborn to Adult

Mazyar Amin; Victoria P. Le; Jessica E. Wagenseil

The large conducting arteries in vertebrates are composed of a specialized extracellular matrix designed to provide pulse dampening and reduce the work performed by the heart. The mix of matrix proteins determines the passive mechanical properties of the arterial wall(1). When the matrix proteins are altered in development, aging, disease or injury, the arterial wall remodels, changing the mechanical properties and leading to subsequent cardiac adaptation(2). In normal development, the remodeling leads to a functional cardiac and cardiovascular system optimized for the needs of the adult organism. In disease, the remodeling often leads to a negative feedback cycle that can cause cardiac failure and death. By quantifying passive arterial mechanical properties in development and disease, we can begin to understand the normal remodeling process to recreate it in tissue engineering and the pathological remodeling process to test disease treatments. Mice are useful models for studying passive arterial mechanics in development and disease. They have a relatively short lifespan (mature adults by 3 months and aged adults by 2 years), so developmental(3) and aging studies(4) can be carried out over a limited time course. The advances in mouse genetics provide numerous genotypes and phenotypes to study changes in arterial mechanics with disease progression(5) and disease treatment(6). Mice can also be manipulated experimentally to study the effects of changes in hemodynamic parameters on the arterial remodeling process(7). One drawback of the mouse model, especially for examining young ages, is the size of the arteries. We describe a method for passive mechanical testing of carotid arteries from mice aged 3 days to adult (approximately 90 days). We adapt a commercial myograph system to mount the arteries and perform multiple pressure or axial stretch protocols on each specimen. We discuss suitable protocols for each age, the necessary measurements and provide example data. We also include data analysis strategies for rigorous mechanical characterization of the arteries.


Biomechanics and Modeling in Mechanobiology | 2014

Measuring, reversing, and modeling the mechanical changes due to the absence of Fibulin-4 in mouse arteries

Victoria P. Le; Yoshito Yamashiro; Hiromi Yanagisawa; Jessica E. Wagenseil

Mice with a smooth muscle cell (SMC)-specific deletion of Fibulin-4 (SMKO) show decreased expression of SMC contractile genes, decreased circumferential compliance, and develop aneurysms in the ascending aorta. Neonatal administration of drugs that inhibit the angiotensin II pathway encourages the expression of contractile genes and prevents aneurysm development, but does not increase compliance in SMKO aorta. We hypothesized that multidimensional mechanical changes in the aorta and/or other elastic arteries may contribute to aneurysm pathophysiology. We found that the SMKO ascending aorta and carotid artery showed mechanical changes in the axial direction. These changes were not reversed by angiotensin II inhibitors, hence reversing the axial changes is not required for aneurysm prevention. Mechanical changes in the circumferential direction were specific to the ascending aorta; therefore, mechanical changes in the carotid do not contribute to aortic aneurysm development. We also hypothesized that a published model of postnatal aortic growth and remodeling could be used to investigate mechanisms behind the changes in SMKO aorta and aneurysm development over time. Dimensions and mechanical behavior of adult SMKO aorta were reproduced by the model after modifying the initial component material constants and the aortic dilation with each postnatal time step. The model links biological observations to specific mechanical responses in aneurysm development and treatment.


Journal of Visualized Experiments | 2012

Measuring Left Ventricular Pressure in Late Embryonic and Neonatal Mice

Victoria P. Le; Attila Kovács; Jessica E. Wagenseil

Blood pressure increases significantly during embryonic and postnatal development in vertebrate animals. In the mouse, blood flow is first detectable around embryonic day (E) 8.5(1). Systolic left ventricular (LV) pressure is 2 mmHg at E9.5 and 11 mmHg at E14.5(2). At these mid-embryonic stages, the LV is clearly visible through the chest wall for invasive pressure measurements because the ribs and skin are not fully developed. Between E14.5 and birth (approximately E21) imaging methods must be used to view the LV. After birth, mean arterial pressure increases from 30 - 70 mmHg from postnatal day (P) 2 - 35(3). Beyond P20, arterial pressure can be measured with solid-state catheters (i.e. Millar or Scisense). Before P20, these catheters are too big for developing mouse arteries and arterial pressure must be measured with custom pulled plastic catheters attached to fluid-filled pressure transducers(3) or glass micropipettes attached to servo null pressure transducers(4). Our recent work has shown that the greatest increase in blood pressure occurs during the late embryonic to early postnatal period in mice(5-7). This large increase in blood pressure may influence smooth muscle cell (SMC) phenotype in developing arteries and trigger important mechanotransduction events. In human disease, where the mechanical properties of developing arteries are compromised by defects in extracellular matrix proteins (i.e. Marfans Syndrome(8) and Supravalvular Aortic Stenosis(9)) the rapid changes in blood pressure during this period may contribute to disease phenotype and severity through alterations in mechanotransduction signals. Therefore, it is important to be able to measure blood pressure changes during late embryonic and neonatal periods in mouse models of human disease. We describe a method for measuring LV pressure in late embryonic (E18) and early postnatal (P1 - 20) mice. A needle attached to a fluid-filled pressure transducer is inserted into the LV under ultrasound guidance. Care is taken to maintain normal cardiac function during the experimental protocol, especially for the embryonic mice. Representative data are presented and limitations of the protocol are discussed.


Physiological Reports | 2014

Fibulin‐5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation

Victoria P. Le; Kellie V. Stoka; Hiromi Yanagisawa; Jessica E. Wagenseil

The large arteries serve as compliant vessels that store energy during systole and return it during diastole. This function is made possible by the elastic fibers in the arterial wall that are assembled during late embryonic and early postnatal development from various proteins, including fibulin‐5. Mice and humans with insufficient amounts of fibulin‐5 have reduced arterial compliance as adults. Reduced compliance of the large arteries is correlated with hypertension, reduced cardiac function, and an increased risk of death from cardiac and cardiovascular disease. The goal of this study was to quantify arterial compliance, blood pressure, and left ventricular (LV) function from early postnatal development to young adulthood in fibulin‐5 null (Fbln5−/−) mice to determine the effects of reduced arterial compliance during this critical period of elastic fiber assembly. We find that ascending aorta compliance is reduced as early as postnatal day (P) 7 and carotid artery compliance is reduced by P21 in Fbln5−/− mice. We did not find significant increases in systolic blood pressure by P60, but pulse pressures are increased by P21 in Fbln5−/− mice. LV systolic function, as measured by ejection fraction and fractional shortening, is unaffected in Fbln5−/− mice. However, LV diastolic function, as measured by tissue Doppler imaging, is compromised at all ages in Fbln5−/− mice. We propose that Fbln5−/− mice represent a suitable model for further studies to determine mechanistic relationships between arterial compliance and LV diastolic function.


Journal of the Royal Society Interface | 2015

Mechanical factors direct mouse aortic remodelling during early maturation.

Victoria P. Le; Jeffrey K. Cheng; Jungsil Kim; Marius Catalin Staiculescu; Shawn W. Ficker; Saahil Sheth; Siddharth A. Bhayani; Robert P. Mecham; Hiromi Yanagisawa; Jessica E. Wagenseil

Numerous diseases have been linked to genetic mutations that lead to reduced amounts or disorganization of arterial elastic fibres. Previous work has shown that mice with reduced amounts of elastin (Eln+/−) are able to live a normal lifespan through cardiovascular adaptations, including changes in haemodynamic stresses, arterial geometry and arterial wall mechanics. It is not known if the timeline and presence of these adaptations are consistent in other mouse models of elastic fibre disease, such as those caused by the absence of fibulin-5 expression (Fbln5−/−). Adult Fbln5−/− mice have disorganized elastic fibres, decreased arterial compliance and high blood pressure. We examined mechanical behaviour of the aorta in Fbln5−/− mice through early maturation when the elastic fibres are being assembled. We found that the physiologic circumferential stretch, stress and modulus of Fbln5−/− aorta are maintained near wild-type levels. Constitutive modelling suggests that elastin contributions to the total stress are decreased, whereas collagen contributions are increased. Understanding how collagen fibre structure and mechanics compensate for defective elastic fibres to meet the mechanical requirements of the maturing aorta may help to better understand arterial remodelling in human elastinopathies.


Journal of The Mechanical Behavior of Biomedical Materials | 2015

Critical buckling pressure in mouse carotid arteries with altered elastic fibers.

Callan M. Luetkemeyer; Rhys H. James; Siva Teja Devarakonda; Victoria P. Le; Qin Liu; Hai Chao Han; Jessica E. Wagenseil

Arteries can buckle axially under applied critical buckling pressure due to a mechanical instability. Buckling can cause arterial tortuosity leading to flow irregularities and stroke. Genetic mutations in elastic fiber proteins are associated with arterial tortuosity in humans and mice, and may be the result of alterations in critical buckling pressure. Hence, the objective of this study is to investigate how genetic defects in elastic fibers affect buckling pressure. We use mouse models of human disease with reduced amounts of elastin (Eln+/-) and with defects in elastic fiber assembly due to the absence of fibulin-5 (Fbln5-/-). We find that Eln+/- arteries have reduced buckling pressure compared to their wild-type controls. Fbln5-/- arteries have similar buckling pressure to wild-type at low axial stretch, but increased buckling pressure at high stretch. We fit material parameters to mechanical test data for Eln+/-, Fbln5-/- and wild-type arteries using Fung and four-fiber strain energy functions. Fitted parameters are used to predict theoretical buckling pressure based on equilibrium of an inflated, buckled, thick-walled cylinder. In general, the theoretical predictions underestimate the buckling pressure at low axial stretch and overestimate the buckling pressure at high stretch. The theoretical predictions with both models replicate the increased buckling pressure at high stretch for Fbln5-/- arteries, but the four-fiber model predictions best match the experimental trends in buckling pressure changes with axial stretch. This study provides experimental and theoretical methods for further investigating the influence of genetic mutations in elastic fibers on buckling behavior and the development of arterial tortuosity.


Volume 1B: Extremity; Fluid Mechanics; Gait; Growth, Remodeling, and Repair; Heart Valves; Injury Biomechanics; Mechanotransduction and Sub-Cellular Biophysics; MultiScale Biotransport; Muscle, Tendon and Ligament; Musculoskeletal Devices; Multiscale Mechanics; Thermal Medicine; Ocular Biomechanics; Pediatric Hemodynamics; Pericellular Phenomena; Tissue Mechanics; Biotransport Design and Devices; Spine; Stent Device Hemodynamics; Vascular Solid Mechanics; Student Paper and Design Competitions | 2013

Characterization of Cardiac Function and Arterial Mechanics During Early Postnatal Development in Fibulin-5 Null Mice

Victoria P. Le; Hiromi Yanagisawa; Jessica E. Wagenseil

Fibulin-5 is an extracellular matrix protein that interacts with other proteins during a complex process that results in elastic fiber formation from the elastin precursor, tropoelastin [1]. Elastic fibers are an important component of tissues requiring elasticity, including large arteries, lungs and skin. In mice lacking fibulin-5 (Fbln5−/−), these tissues contain disorganized elastic fibers and exhibit decreased elasticity [2]. The phenotype of Fbln5−/− mice is similar to that of humans with cutis laxa, a connective tissue disorder characterized by loose skin and narrow arteries with reduced compliance.Copyright


ASME 2011 Summer Bioengineering Conference, Parts A and B | 2011

Mechanics and Modeling of Postnatal Arterial Development in Wild-Type and Elastin-Insufficient Mice

Jeffrey K. Cheng; Victoria P. Le; Robert P. Mecham; Jessica E. Wagenseil

Large arteries in vertebrates serve as elastic reservoirs that store a portion of the blood volume with systole and discharge it during diastole. This function is made possible by the combination of extracellular matrix (ECM) proteins deposited by the smooth muscle cells (SMCs) in the arterial wall. Elastin and collagen expression in mice is first detectable around embryonic day 14 and peaks around postnatal day (P) 14, returning to baseline levels by P30. During this time, pressure and cardiac output increase significantly before leveling off ∼P30 [1]. Hence, the protein amounts and consequent mechanical properties of the arterial wall change simultaneously with the applied hemodynamic loads in a complicated and unknown feedback loop.Copyright

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Robert P. Mecham

Washington University in St. Louis

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Jeffrey K. Cheng

Washington University in St. Louis

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Mazyar Amin

University of Washington

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Yoshito Yamashiro

University of Texas Southwestern Medical Center

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Christina L. Papke

University of Texas Southwestern Medical Center

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Hai Chao Han

University of Texas at San Antonio

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Jianbin Huang

University of Texas Southwestern Medical Center

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