Download or read book The Aortic Valve Endothelial Cell written by Scott Andrew Metzler and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The aortic valve (AV) functions in arguably the most demanding mechanical environment in the body. The AV experiences fluid shear stress, cyclic pressure and mechanical strain in vivo. Recent evidence has shown the progression of degenerative aortic valve disease (AVD) to be an active cellular mediated process, altering the conception of the AV as a passive tissue. AVD has shown a strong correlation with altered hemodynamics and tissue mechanics. Aortic valve endothelial cells (AVECs) line the fibrosa (aortic facing) and ventricularis (left ventricle facing) surfaces of the valve. AVECs sense and respond to circulating stimuli in the blood stream while maintaining a non-thrombogenic layer. AVEC activation has been implicated in the initiation and progression of AVD, but the role of cyclic strain has yet to be elucidated. The hypothesis of this dissertation is that altered mechanical forces have a causal relationship with aortic valvular endothelial cell activation. To test this hypothesis 1) the role of in vitro cyclic strain in regulating expression of pro-inflammatory adhesion molecule was elucidated 2) cyclic strain-dependent activation of side-specific aortic valve endothelial cells was investigated 3) a novel stretch bioreactor was developed to dramatically increase the ability to correlate valvular endothelium response to physiologically relevant applied planar biaxial loads. The results from this study further the field of heart valve mechanobiology by correlating AVEC physiological and pathophysiological function to cellular and tissue level strain. Elucidating the AVEC response to an altered mechanical environment may result in novel clinical diagnostic and therapeutic approaches to the initiation and progression of degenerative AVD. Furthermore, a cardiovascular health outreach program, Bulldogs for Heart Health, has been designed and implemented to combat the startling rise in childhood obesity in the state of Mississippi. It is the hope that these results, novel methods, and outreach initiatives developed will significantly impact the study of the mechanobiology of the aortic valve endothelial cell and potential treatment and prevention of cardiovascular disease.

Download or read book Aortic Valve Endothelial Cells and Adhesion Molecules written by and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Children with congenital heart defects and patients with faulty or failing valves have the need for a suitable aortic heart valve replacement. Current treatment options have several downfalls and heavy investigation is being done into the design of an engineered valve to find an alternative that would alleviate many of these issues. Understanding the physiology of how cells interact in vivo is crucial to the construction of such valve. This study investigates the effect of cyclic strain in aortic valve endothelial cells on the adhesion molecules, PECAM-1, [Beta]1-Integrin, VE-Cadherin and Vinculin. Experiments found that cyclic strain plays a role in the development of cell/cell and cell/extracellular matrix adhesions and junctions and is extremely important in the pre-conditioning of a tissue engineered construct. Without this strain the new valve would be more susceptible to inflammation, injury or possible failure after being implanted into the patient.

Download or read book Calcific Aortic Valve Disease written by Elena Aikawa and published by BoD – Books on Demand. This book was released on 2013-06-12 with total page 544 pages. Available in PDF, EPUB and Kindle. Book excerpt: Due to population aging, calcific aortic valve disease (CAVD) has become the most common heart valve disease in Western countries. No therapies exist to slow this disease progression, and surgical valve replacement is the only effective treatment. Calcific Aortic Valve Disease covers the contemporary understanding of basic valve biology and the mechanisms of CAVD, provides novel insights into the genetics, proteomics, and metabolomics of CAVD, depicts new strategies in heart valve tissue engineering and regenerative medicine, and explores current treatment approaches. As we are on the verge of understanding the mechanisms of CAVD, we hope that this book will enable readers to comprehend our current knowledge and focus on the possibility of preventing disease progression in the future.

Download or read book Initiating Mechanisms of Aortic Valve Disease written by Emily Jean Farrar and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The objective of this thesis was to unveil initiating mechanisms of aortic valve disease, a serious and prevalent cardiovascular pathology affecting 2.8% of Americans over the age of 75. Currently, valve disease has no known causes and no existing treatments except for cardiothoracic surgery. Identification of initiating mechanisms will lead to new diagnostic markers and treatment strategies that would allow for early intervention and eventually the prevention of valve disease. This work primarily focuses on the influence of the inflammatory cytokine tumor necrosis factor-[alpha] (TNF[alpha]) on the endothelial cells that line the aortic valve. By focusing on inflammation and the endothelium, both "first responders" to disease conditions in the valve environment, we hoped to unveil new mechanisms that could govern early stages of the disease. In this thesis, we have demonstrated that TNF[alpha] causes adult valve endothelial cells to produce destructive free radicals, dysregulating the delicate oxidate stress state of the valve. TNF[alpha] also drives endothelial cells to become mesenchymal via NF[kappa]B signaling, a reactivation of an embryonic pathway important to shaping the valve leaflets in utero. We further found that NF[kappa]B signaling drives endothelial participation in the later stages of valve calcification, showing in vivo that NF[kappa]B is a critical mediator of valve dysfunction. We have also demonstrated a role for the stem cell transcription factor Oct4 in governing how valve endothelial cells change phenotype throughout disease. These findings have led to improved understanding of how NF[kappa]B and Oct4 govern interstitial cell calcification, in the later stages of valve disease. Finally, we have used the biomechanical engineering strengths of our lab to investigate how the regulation of valve interstitial cell contractility is crucial to progression of calcification in the valve. My hope is that the results presented in this thesis will create a basic science foundation for the development of diagnostics and therapies to help patients suffering from aortic valve disease, especially those ineligible for surgical amelioration. Our in vitro and in vivo findings regarding the role of inflammation in endothelial dysfunction provide new evidence for the design of drugs targeting the NF[kappa]B pathway for aortic valve disease.

Download or read book Endothelial Regulation of Valve Interstitial Cells in Calcific Aortic Valve Disease written by Jennifer Marie Richards and published by . This book was released on 2015 with total page 219 pages. Available in PDF, EPUB and Kindle. Book excerpt: Calcified aortic valve disease (CAVD) is an increasingly prevalent pathology that often manifests in the degenerative calcification of the valve tissue. Currently, the only treatment for aortic valve calcification is surgical intervention, and a clinically useful molecular signature of CAVD progression has not yet been found. Recent clinical trials testing lipid-lowering therapies were ineffective against aortic stenosis progression, which emphasizes that CAVD may undergo a distinctly different pathogenesis from that of atherosclerosis. While CAVD is no longer believed to be a passive degenerative process, the cellular mechanisms by which the valve calcifies are not wholly understood. There remains a need to understand cellular mechanisms of valve pathogenesis, as well as an in-depth analysis of the altogether unique calcified lesions that form as a result of the disease. The focus of this dissertation was the development of a 3D construct in which the interplay between valve endothelial (VEC) and valve interstitial cells (VIC) could be illuminated in various calcification-prone environments. The completion of this work yielded insights into cellular responses to osteogenic, mineralized, and altered mechanical environments, which could be used to identify potential therapeutic targets or early diagnosis strategies in the future. A 3D hydrogel construct was first developed for the co-culture of interstitial and endothelial cells, which is more physiologically relevant than current 2D models. Under osteogenic conditions, endothelial cells were found to have a protective effect against VIC activation and calcification (Chapter 2). Next, the mineralized lesions and surrounding organic tissue in calcified valves were characterized and found to have a heterogeneous composition of apatite and calcium phosphate mineral crystals (Chapter 3). These findings prompted the use of synthetically derived hydroxyapatite nanoparticles of two different maturation states in order to better evaluate cellular response to a highly mineralized matrix, characteristic of later stages of valve disease (Chapter 4). Finally, the effects of an altered mechanical environment, as is typical in valve disease, were examined by increasing mechanical tension in 3D hydrogel constructs and applying cyclic mechanical strain (Chapter 5). Overall, this body of work has made significant advancements in understanding individual and incorporative cellular responses to osteogenic, mineralized and mechanical 3D environments. This work has contributed to the emerging appreciation that 3-dimensional multi-cellular co-cultures are vital to mechanistic understanding of valve pathogenesis. Our 3D platform shows great promise for future studies, and could enable direct screening of molecular mechanisms of calcification and testing of potential molecular inhibitors.

Download or read book Endothelial Cell Biology in Health and Disease written by M. Simionescu and published by Springer Science & Business Media. This book was released on 2013-11-11 with total page 460 pages. Available in PDF, EPUB and Kindle. Book excerpt: Although blood capillaries were first observed through a flea-lens microscope by Malpighi in 1661,200 more years elapsed before the cellular nature of the vessel wall was conclusively demonstrated. Beginning with the middle of the 19th cen tury, our knowledge of the histological organization of blood vessels has steadily increased. However, the endothelium, which for a long time was considered to be just an inert barrier lining, had been barely explored until three decades ago. Since then, there has been an upsurge of interest in the fine structure and function of endothelial cells. Intense in vivo and in vitro investigations have revealed that the endothelial cell is a key element in a wide variety of normal activities and diseases. A large number of investigators and laboratories have been attracted to endothelial cell research, thus supporting the expansion of the continuously grow ing and diversifying field of endotheliology. The number of articles published annually on this subject has increased from a few score at the beginning of the 1970s to more than a thousand in recent years, and an increasing number of journals, books, societies, and symposia focused primarily on the vascular en dothelium have marked the last decade.

Download or read book Mechanobiology of the Endothelium written by Helim Aranda-Espinoza and published by CRC Press. This book was released on 2015-02-25 with total page 278 pages. Available in PDF, EPUB and Kindle. Book excerpt: The endothelium is an excellent example of where biology meets physics and engineering. It must convert mechanical forces into chemical signals to maintain homeostasis. It also controls the immune response, drug delivery through the vasculature, and cancer metastasis. Basic understanding of these processes is starting to emerge and the knowledge ga

Download or read book Advances in Heart Valve Biomechanics written by Michael S. Sacks and published by Springer. This book was released on 2019-04-08 with total page 487 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book covers the latest research development in heart valve biomechanics and bioengineering, with an emphasis on novel experimentation, computational simulation, and applications in heart valve bioengineering. The most current research accomplishments are covered in detail, including novel concepts in valvular viscoelasticity, fibril/molecular mechanisms of tissue behavior, fibril kinematics-based constitutive models, mechano-interaction of valvular interstitial and endothelial cells, biomechanical behavior of acellular valves and tissue engineered valves, novel bioreactor designs, biomechanics of transcatheter valves, and 3D heart valve printing. This is an ideal book for biomedical engineers, biomechanics, surgeons, clinicians, business managers in the biomedical industry, graduate and undergraduate students studying biomedical engineering, and medical students.

Download or read book From Biology to Clinical Management An Update on Aortic Valve Disease 2nd Edition written by Cécile Oury and published by Frontiers Media SA. This book was released on 2020-03-04 with total page 58 pages. Available in PDF, EPUB and Kindle. Book excerpt: Calcific aortic valve stenosis is the most frequent valvular heart disease in Western countries, affecting up to 13% of individuals over 75 years. The disease is associated with considerable morbidity and mortality. It is characterized by fibro-calcification of aortic valve cusps and concomitant left ventricular remodelling due to chronic pressure overload, which can evolve into overt heart failure. It progresses very slowly until the onset of symptoms, the indication for aortic valve replacement. Today, about 300,000 aortic valve replacements are performed annually worldwide, either via surgery or transcatheter implantation. This is the only treatment shown to improve survival. There is no pharmacological treatment to prevent or slow disease progression. Major risk factors include older age, congenital anomalies of the aortic valve (bicuspid valve), male gender, hypertension, dyslipidaemia, smoking, and diabetes. However, how these factors contribute to the disease in unclear. Due to the disease itself, patients are at increased risk of both thrombosis and bleeding, which, in addition to advanced age and comorbidities, makes antithrombotic management of these patients difficult. Regarding valve prostheses, the ideal prosthesis either mechanical or biological still does not exist. Clinically available prostheses can lead to major complications, thrombosis or infection, which necessitate reoperation or cause death in 50-60% of patients within 10 years post-implantation. Hence, there are major unmet medical needs in CAVS and more basic and translational research is definitely required. Our Research Topic depicts major challenges and research paths that could be followed to address these major health needs.

Download or read book The Effects of Steady Laminar Shear Stress on Aortic Valve Cell Biology written by Jonathan Talbot Butcher and published by . This book was released on 2004 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Aortic valve disease (AVD) affects millions of people of all ages around the world. Current treatment for AVD consists of valvular replacement with a non-living prosthetic valve, which is incapable of growth, self-repair, or remodeling. While tissue engineering has great promise to develop a living heart valve alternative, success in animal models has been limited. This may be attributed to the fact that understanding of valvular cell biology has not kept pace with advances in biomaterial development. Aortic valve leaflets are exposed to a complex and dynamic mechanical environment unlike any in the vasculature, and it is likely that native endothelial and interstitial cells respond to mechanical forces differently from other vascular cells. The objective of this thesis was to compare valvular cell phenotype to vascular cell phenotype, and assess the influence of steady shear stress on valvular cell biology. This thesis demonstrates that valvular endothelial cells respond differently to shear than vascular endothelial cells, by aligning perpendicular to the direction of steady shear stress, and by the differential regulation of hundreds of genes in both static and fluid flow environments. Valvular interstitial cells expressed a combination of contractile and synthetic phenotypes not mimicked by vascular smooth muscle cells. Two three-dimensional leaflet models were developed to assess cellular interactions and the influences of steady laminar shear stress. Valvular co-culture models exhibited a physiological response profile, while interstitial cell-only constructs behaved more pathologically. Steady shear stress enhanced physiological functions of valvular co-cultures, but increased pathological response of interstitial cell-only constructs. These results showed that valvular cells, whether cultured separately or together, behaved distinctly different from vascular cells. It was also determined that shear stress alone cannot induce tissue remodeling to more resemble native valve leaflets. The leaflet models developed in this thesis can be used in future experiments to explore valvular cell biology, assess the progression of certain forms AVD, and develop targeted diagnostic and therapeutic strategies to hopefully eliminate the need for valvular replacement entirely.

Download or read book Biology of Endothelial Cells written by Eric A. Jaffe and published by Springer. This book was released on 1984-03-31 with total page 480 pages. Available in PDF, EPUB and Kindle. Book excerpt: The participation of endothelial cells in various physiologic and pathologic processes has been hypothesized since before the turn of the century. However, until recently, direct evidence for endothelial involvement in these processes has been extremely difficult to obtain due to the inability to study endothelial cell function in vitro. Though the possibility of using cultured endothelial cells to study endothelial cell function in vitro was recognized many years ago, the inability to culture unambiguously identifiable endothelial cells limited investigators in their studies of endothelial function. As a result, the field of endothelial cell biology lay relatively fallow for many years. The development in the early 1970's of routine and easily implemented methods for culturing human endothelial cells and the demonstration that cultured endothelial cells synthesized a physiologically relevant protein, Factor VIII/von Willebrand Factor, quickly changed this state of affairs. Over the following decade the scope of endothelial cell research rapidly widened, spreading in a number of directions. First, methods were developed to culture endothelial cells from a variety of species. Second, methods were developed to culture endothelial cells from different organs and types of blood vessels (arteries, veins, and capillaries) within a single species. Third, and most important, investigators began using cultured endothelial cells as tools to study the potential involvement of endothelial cells in a wide assortment of biologically interesting processes. The net result has been a tremendous increase in our understanding of endothelial cell function.

Download or read book Coregulatory Mechanisms of Cellular Recruitment in Fibrocalcific Aortic Valve Disease written by Terence William Gee and published by . This book was released on 2020 with total page 207 pages. Available in PDF, EPUB and Kindle. Book excerpt: The objective of this thesis was to develop and implement in vitro and in vivo model systems to understand complex, collaborative cellular mechanisms underpinning calcific aortic valve disease, an increasingly prevalent cardiovascular pathology lacking effective early diagnostic and therapeutic strategies save for invasive prosthetic replacement surgery. Through this work we have identified the role for canonical NF_B functioning as a "gatekeeper" for valve endothelial cell initiation and active participation in degenerative tissue calcification and identified this pathway as a promising therapeutic target for further preclinical evaluation. We further developed an in vitro platform through which cocultured endothelial and interstitial cells develop emergent, macro-calcific lesion features with underlying cellular and molecular signaling features recapitulative of the human etiology. Through these respective works we identify a subpopulation of endothelial derived mesenchymal progenitors, likely derived via post-natal reactivation of the Endothelial-to-Mesenchymal Transformation process, as being crucial role-players of the pathogenic process. Lastly, we build upon these systems to interrogate the diverse role of the Notch cell-fate decision making pathway in regulating valvular cell calcific transformation and matrix remodeling activity. The hope is that from the knowledge gleaned from this work, and by establishing these model systems, we can better understand the pathobiology of this and identify effective diagnostic markers for the disease or therapeutic candidates for its treatment.

Download or read book Discovery of Shear and Side dependent Messenger RNAs and MicroRNAs in Aortic Valvular Endothelium written by Casey Jane Holliday and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Aortic valve (AV) disease is a major cause of cardiovascular-linked deaths globally. In addition, AV disease is a strong risk factor for additional cardiovascular events; however, the mechanism by which it initiates and progresses is not well-understood. We hypothesize that low and oscillatory flow is present on the fibrosa side of the AV and stimulates ECs to differentially regulate microRNA (miRNA) and mRNAs and influence AV disease progression. This hypothesis was tested employing both in vitro and in vivo approaches, high throughput microarray and pathway analyses, as well as a variety of functional assays. First, we isolated and characterized side-dependent, human aortic valvular endothelial cells (HAVECs). We found that HAVECs express both endothelial cell markers (VE-Cadherin, vWF, and PECAM) as well as smooth muscle cell markers (SMA and basic calponin). Using microarray analysis on sheared, side-specific HAVECs, we identified side- and shear-induced changes in miRNA and mRNA expression profiles. More specifically, we identified over 1000 shear-responsive mRNAs which showed robust validation (93% of those tested). We then used Ingenuity Pathway Analysis to identify key miRNAs, including those with many relationships to other genes (for example, thrombospondin and I & B) and those that are members of over-represented pathways and processes (for example, sulfur metabolism). Furthermore, we validated five shear-sensitive miRNAs: miR-139-3p, miR-148a, miR-187, miR-192, and miR-486-5p and one side-dependent miRNA, miR-370. To prioritize these miRNAs, we performed in silico analysis to group these key miRNAs by cellular functions related to AV disease (including tissue remodeling, inflammation, and calcification). Next, to compare our in vitro HAVEC results in vivo, we developed a method to isolate endothelial-enriched, side-dependent total RNA and identify and validate side-dependent (fibrosa vs. ventricularis) miRNAs in porcine aortic valvular endothelium. From this analysis, we discovered and validated eight side-dependent miRNAs in porcine endothelial-enriched AV RNA, including one miRNA previously identified in vitro, miR-486-5p. Lastly, we determined the relationship between important miRNAs (specifically miR-187 and miR-486-5p) and AV disease by modulating levels of miRNAs and performing functional assays. Preliminary studies overexpressing miR-187 in HAVECs have shown a reduction in inflammatory state through monocyte adhesion (p

Download or read book The Role of Bone Morphogenic Proteins in Human Aortic Valvular Endothelial Cells written by Randall Francis Ankeny and published by . This book was released on 2010 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: In the United States alone, there are nearly 49,000 aortic valvular repairs or replacements each year, and this number is expected to rise. Unlike atherosclerosis, the molecular mechanisms contributing to this side-dependent disease development are limited, which contributes to the lack of therapeutic treatments. Once clinically manifested, options for treatment are limited to valvular replacement or repair. Therefore understanding the mechanobiology and cellular responses in aortic valves may provide important information for disease development and possible biomarkers or therapeutic treatments.

Download or read book The Influence of Normal Physiological Forces on Porcine Aortic Heart Valves in a Sterile Ex vivo Pulsatile Organ Culture System written by Suchitra Konduri and published by . This book was released on 2005 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The aortic valve functions in a complex mechanical environment which leads to force dependent cellular and tissue responses. Characterization of these responses provides a fundamental understanding of valve pathogenesis. The aim of this work was to develop an ex vivo organ culture system capable of simulating physiological aortic pressures and flow rates, and study the biological characteristics of native porcine aortic valves cultured in the system. Collagen, sGAG and elastin content of the valve leaflets were measured and cusp morphology, cell phenotype, cell proliferation and apoptosis were examined. Presence of endothelial cells (ECs) on the leaflet surface was also evaluated. The differences in collagen, sGAG and elastin contents were not significant (p>0.05) between the cultured and fresh valve leaflets. The cultured valves maintained the structural integrity of the leaflets while preserving the native morphology and cell phenotype. Cell phenotype in leaflets incubated statically under atmospheric conditions decreased compared to fresh and cultured valve leaflets, indicating the importance of mechanical forces in maintaining the natural biology of the valve leaflets. ECs were retained on the surfaces of cultured leaflets with no remodeling of the leaflets. The number of apoptotic cells in the cultured leaflets was significantly (p

Download or read book The Living Aortic Valve written by Ismail El-Hamamsy and published by . This book was released on 2011 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Drug induced Valvular Heart Disease written by Steven Droogmans and published by Nova Biomedical Books. This book was released on 2011 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The notion that drugs can induce valvular heart disease (VHD) has occurred since the sixties and has received a lot of attention in recent years. Overstimulation of the serotonin 2B receptor (5-HT2B) leads to valvular fibroblast proliferation and thickening of the valvular leaflets with reduced mobility and regurgitation as a consequence. This new book focuses on different aspects of this distinct kind of valvulopathy including pathophysiology of drug-induced VHD, histopathological and echocardiographic characteristics, drugs associated with VHD, the influence of cumulative drug dose and risk factors and others.