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Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, HTN, Human Immune System in Health and in Disease, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Resident-cell-based, Scientist: Career considerations, Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged , , , , , , , , , on August 24, 2012| 17 Comments »

Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

 

Curator and Author: Aviva Lev-Ari, PhD, RN

 

Classification of Fast Acting Therapies for Patients at High Risk for Macrovascular events

Macrovascular Disease – Therapeutic Potential of cEPCs

 

The two leading therapy classes are:

  1. Cell-based Therapies for angiogenesis and myocardial regeneration
  2. Intracoronary Delivery of Autologous Bone Marrow originating cells to restore Ischemic Tissue

The European Meeting on Vascular Medicine and Biology is a biannual international conference. The 3rd European Meeting on Vascular Medicine and Biology, took place in September 2005 and the next conference will be in 2007. All abstract presentations are published in Supplement 2, JOURNAL OF VASCULAR RESEARCH, Volume 42, 2005.

Review of 355 abstracts of posters presented at the conference has identified the following twenty Research Frontiers in Vascular Biology and Vascular Disease.

One abstract is of special interest to the line of research which focus on endogenous augmentation of cEPCs and to reduction of CVD risk by endogenous induction of regression of atherosclerotic plaques. It was selected by being judged to have the highest potential for commercialization and the potential to replace several therapeutic agents with higher efficacy.

P119 IgG1 antibodies against oxLDL epitopes induce regression of advanced atherosclerotic plaques in LDLR-/- APOBEC mice.

A. Schiopu1, B. Jansson2, P.K. Shah3, R. Carlsson3, J. Nilsson1, G. Nordin Fredrikson1Department of Medicine, Malmö University Hospital, Lund University, Malmö, SE; 2 BioInvent International AB, Lund, SE; 3 Atherosclerosis Research Center, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, US.

Objective: The purpose of our study was to assess the effects of recombinant human IgG1 antibodies against specific oxLDL epitopes on advanced atherosclerotic lesions in mice.

Methods: We have tested 2 recombinant human IgG1 antibodies directed to malondialdehyde (MDA)-modified ApoB-100 peptide sequences. Three weekly 1 mg antibody doses were injected intraperitoneally starting at 25 weeks in LDLR-/-Apobec mice, which were then sacrificed at 29 weeks of age. IgG1 antibodies directed against fluorescein isothiocyanate, which do not bind to either native or oxidized LDL, and a

baseline group sacrificed at 25 weeks of age, to asses plaque status before immunization, were used as controls.

Results: Both antibodies induced a significant regression of already present atherosclerotic plaques in the descending aorta as compared to baseline. This effect was not present in the isotype control group. The changes did not depend on alterations in weight, cholesterol or triacylglycerol content in mice plasma.

Conclusions: The present study suggests that antibody treatment has the ability to reduce the extent of already present, advanced atherosclerotic lesions. Passive immunization with antibodies directed against oxLDL epitopes might constitute a future fast acting therapy for patients at high risk for acute cardiovascular events.

Twenty Research Frontiers in Vascular Medicine of Human Endothelium

 

Research Frontiers in Vascular Biology and Vascular Disease 

 

   

International Research Projects
Stem Cell biology Embryonic stem cells in cardiovascularrepairEarly differentiation of human endothelial progenitor cellsVessels transmigration of stem cells depends on activation of the endothelium.

Interaction of embryonal endothelial progenitor cells with platelets

Role of smooth muscle cell progenitors on atherosclerotic plaque development and stability.

 
Ischemia  and Reperfusion Connexin 43 and myocardial ischemia/reperfusioninjuryEndothelialreperfusion injuryA possible role for hypoxia-inducible factor 1• in protection against reperfusion injury

 
Genetic Basis of Vascular Disease Cardiovascular genomics and oxidative stressNox1 mediates basic fibroblast growth factor induced vascular smooth muscle cell migrationReactive oxygen species upregulate NOX4, but not NOX2, in endothelial cells

Induction of prolyl hydroxylase 2 by nitric oxide interferes with the hypoxia induced feedback loop of HIF-1• regulation

Protein disulfide isomerase is a central

regulator of NADPH oxidase activity

 
Inflammation Inflammatory mediatorsofvascularInflammationIsoprostanes inhibit in vitro migration and tube formation of endothelial cells via the thromboxane A2 receptor.

Heme oxygenase-1-dependent and

-independent regulation of angiogenic and inflammatory genes expression in human microvascular endothelial cells

 
Tissue Engineering Engineered heart tissueEndothelial tissue engineeringBlood vessel growth and remodeling in in-vivo tissue engineering

The effects of cyclic strain on the cytoskeleton of vascular smooth muscle cells

 
Atherosclerosis Imaging Experimental In vivo imaging ofatherosclerosisHoming ofCD34+ progenitor cells to sites ofangiogenic tube formation using real-time video microscopy.Relation between lipoprotein(a) and fibrinogen and serial intravascular ultrasound plaque progression in left main stems

Cardiovascular Development Controlled by Fluid Shear Stress. A Functionomic Approach.

Dynamics in microvascular alterations in UCP/DTA mice in vivo – from metabolic syndrome to diabetes mellitus type 2
Vascular Cell Signaling TGF-beta in endothelial cell functionandvascular developmentVEGF signaling

 
Atherosclerosis (Clinical / In Vivo) Pathophysiology of cigarette smoking-inducedatherosclerosisThe homeostatic benefits of plaque ruptureEarly coronary atherogenesis as a

consequence of chronic in-vivo proteasome inhibition.

 
Renin-Angiotensin System ACE inhibitorsstimulate endothelialCOX-2expression by aJNK-dependent ACE signalling pathway.A new ACE on the table: ACE2 expression in human atherosclerosis

Role of the ACE gene in renal and vascular complications of diabetes mellitus, experimental study in the mouse.

Bone marrow molecular alterations after

myocardial infarction: impact on endothelial progenitor cells and modulation by ACE inhibition or statin treatment.

Anti-inflammatory properties of Ramiprilat: reduction of monocyte adhesion to angiotensin II-stimulated endothelium is associated with AT1 downregulation.

Activation of phospholipase D by angiotensin II in HUVECS and HMVECS
Pathogenesis of Atherosclerosis Metalloproteinases in vascular pathologywhat we know and what we don’t know.
Stem Cell Therapy Functional assessment of circulatingcellsHuman fetal vascular progenitor cellsaccelerate the healing of ischemic diabetic ulcers

Peri-infarct gene transfer of human tissue kallikrein gene prevents left ventricle dysfunction by stimulating

angiogenesis/arteriogenesis and cardiac stem cell activation and by inhibiting cardiomyocyte apoptosis.

 
Genomics / Proteomics in Vascular Biology Genomic analysis of animal modelsforatherosclerosis.Differential gene expression analysis of tube forming and non-tube forming microvascular endothelial cells in vitro, separated by differences in morphology

Proteomic and metabolomic analysis of

atherosclerotic vessels in ApoE-/- mice

Hypoxic angiogenic transcriptome in human keratinocytes and microvascular endothelial cells: macroarray and real-time PCR analysis.

Gene expression profiling of human red blood cells.

 
Oxidant and Lipid Signaling Lipid modifications in atherogenesis.Epoxyeicosatrienoic acids in vascularHomeostasis

Oxidized phospholipids as modulators of

Inflammation
Chemokines — Cell-Cell Interactions Endothelial cell-to-celljunctionsInterplay ofchemokines and platelets invascular cell recruitment

 
Vascular Development Embryonic vesseldeterminationVascular remodeling: differentiation ofarteries, veins and lymph vessels

 
Vascular Aneurysms and VascularDegradation MMP in aneurysmdevelopmentFurin-likeproproteinconvertases regulate membrane type-1 matrixmetalloproteinase in atherosclerosisNon-viral, electroporation mediated gene

transfer of TIMP-1.ATF, a cell-surface directed MMP inhibitor, suppresses intimal hyperplasia in vein grafts more efficiently than TIMP-1 in vivo.

EMMPRIN regulates MMP activity in

cardiovascular cells. Implications in Acute Myocardial Infarction.

NF-kB promotes monocyte adhesion in vessels exposed to high intraluminal pressure
Diabetes Mellitus and InsulinResistance The endothelial cellglycocalyx indiabetesVasocrine signaling and insulin resistanceEarly arteriogenic defects in a diabetic

ischemic hindlimb model

Diabetes-induced overproduction of reactive oxygen species impairs post-ischemic neovascularization

 
Microparticles / Platelets The significance of membranemicroparticles in vascular pathophysiology andintercellularcommunication.Influences of nuclear receptors on platelet function.

Cellular origin of microparticles in human

atherosclerotic plaques

Apoptotic microparticles derived from

endothelial cells, smooth muscle cells and monocytes induce thrombin generation via different pathways
Smooth Muscle Cells Role of epigenetic mechanisms in control of SMC differentiation in development anddiseaseThe cytoskeletal proteinzyxin is amechanosensitive signaltransducer in vascular smooth muscle cells.Leukotriene-induced migration and

proliferation of vascular smooth muscle cells: implications for atherosclerosis and restenosis

 
Stem Cells Transfer of stem cell-derived endothelial cells retardedneointimal lesions in the injured artery.Stimulation ofreendothelialization viarecruitment of endothelial progenitor cells with selective antibodies against progenitor cell surface markers

Caspase-8 activity is essential for endothelial progenitor cell adherence

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Endothelial Differentiation and Morphogenesis of Cardiac Precursors

Posted in Cardiovascular Pharmacogenomics, tagged , , , , , , , , on July 17, 2012| 3 Comments »

Reporter: Sudipta Saha, Ph.D.

 

Beyond characterization of the fundamental anatomy of vascular development, the first investigators in this field participated in one of the classic debates in all of developmental biology: where and when do endothelial cells (and hence blood vessels) arise in the developing embryo? Because blood vessels are first observed in the yolk sac in avian and mammalian embryos. It was initially assumed that all blood vessels arise from extra-embryonic tissues. However, careful histological analysis subsequently indicated that isolated foci of endothelial cells can also be observed in the embryo proper, which suggested that blood vessels arise from an intraembryonic source (specifically, the mesoderm) rather than via colonization. The formation of new blood vessels in the adult organism not only contributed to the progression of diseases such as cancer and diabetic retinopathy but also can be promoted in therapeutic approaches to various ischemic pathologies. Because many of the signals important to blood vessel development during embryogenesis are recapitulated during adult blood vessel formation, much work has been performed to better-understand the molecular control of endothelial differentiation in the developing embryo. Activators and inhibitors of developmental pathways have been tested for their ability to modulate angiogenesis in early phase clinical trials, and in the case of anti-Flk1 antibodies clinical utility has been demonstrated for anti-tumor strategies. Analyses of circulating endothelial progenitor cells, which have angiogenic potential, do indeed suggest that there are similarities in the biology of these cells compared with developmental endothelial precursors. Stem cell therapeutics therefore represents another potential arena for translation of insights from vascular development to clinical practice. Even though our understanding of endothelial development is much richer than it was even a few years ago and despite the potential applications of this knowledge in clinical medicine, there are still a number of key issues on this topic that remain to be resolved. Precisely how early are endothelial precursors specified during development, and what is the nature of this progenitor cell pool? What are the relationships among signaling pathways that specify endothelial fates in a coordinated fashion? Is there a transcriptional hierarchy that regulates vascular development? The answers to these and other questions about endothelial development are likely to be forthcoming in the near future as experimental methods continue to evolve (http://atvb.ahajournals.org/content/25/11/2246.full).

 

The development of the vertebrate heart can be considered an additive process, in which additional layers of complexity have been added throughout the evolution of a simple structure (linear heart tube) in the form of modular elements (atria, ventricles, septa, and valves). Each modular element confers an added capacity to the vertebrate heart and can be identified as individual structures patterned in a precise manner. An understanding of the individual modular steps in cardiac morphogenesis is particularly relevant to congenital heart disease, which usually involves defects in specific structural components of the developing heart. Organ formation requires the precise integration of cell type-specific gene expression and morphological development; both are intertwined in their regulation by transcription factors. Although many transcription factors have been described as regulators of cardiac-specific gene expression, the transcriptional regulation of cardiac morphogenesis is still not well explored. For a transcription factor to be considered directly involved in heart development, it must be expressed in developing heart tissues and exert an influence on processes that impact the morphogenesis of the developing heart. Transcription factors can regulate the expression of other genes in a tissue-specific and quantitative manner and are thus major regulators of embryonic developmental processes. A number of complex transcriptional networks and interactions are involved in the morphogenesis of the developing vertebrate heart. The identities of crucial regulators involved in defined events in cardiogenesis are being uncovered at a rapid rate, but a number of critical questions remain. First and foremost, it is still not known which transcription factors are involved in the earliest differentiation of cardiac cells from the mesoderm. Second, the downstream pathways regulated by transcription factors responsible for key morphogenetic events are still largely unknown. Third, the concept of maintained function or redeployment of functions throughout various stages of development remains to be addressed in detail. The challenge for the future lies in defining pathways downstream from cardiac transcription factors and understanding the intersection of these pathways as the heart develops from a simple patterned structure into a complex multifunctional organ (http://circres.ahajournals.org/content/90/5/509.full).

 

Tissue development and regeneration involve tightly coordinated and integrated processes: selective proliferation of resident stem and precursor cells, differentiation into target somatic cell type, and spatial morphological organization. The role of the mechanical environment in the coordination of these processes is poorly understood. It has been reported that multipotent cells derived from native cardiac tissue continually monitored cell substratum rigidity and showed enhanced proliferation, endothelial differentiation, and morphogenesis when the cell substratum rigidity closely matched that of myocardium. Mechanoregulation of these diverse processes required p190RhoGAP, a guanosine triphosphatase-activating protein for RhoA, acting through RhoA-dependent and -independent mechanisms. Natural or induced decreases in the abundance of p190RhoGAP triggered a series of developmental events by coupling cell-cell and cell-substratum interactions to genetic circuits controlling differentiation (http://www.ncbi.nlm.nih.gov/pubmed/22669846).

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Engineered Microvessels Provide a 3-D Test Bed for Human Diseases

Posted in Biological Networks, Gene Regulation and Evolution, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged , , , , , , , on May 30, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Mice and monkeys don’t develop diseases in the same way that humans do. Nevertheless, after medical researchers have studied human cells in a Petri dish, they have little choice but to move on to study mice and primates.

University of Washington bioengineers have developed the first structure to grow small human blood vessels, creating a 3-D test bed that offers a better way to study disease, test drugs and perhaps someday grow human tissues for transplant.

The findings are published this week in the Proceedings of the National Academy of Sciences.

“In clinical research you just draw a blood sample,” said first author Ying Zheng, a UW research assistant professor of bioengineering. “But with this, we can really dissect what happens at the interface between the blood and the tissue. We can start to look at how these diseases start to progress and develop efficient therapies.”

Zheng first built the structure out of the body’s most abundant protein, collagen, while working as a postdoctoral researcher at Cornell University. She created tiny channels and injected this honeycomb with human endothelial cells, which line human blood vessels.

During a period of two weeks, the endothelial cells grew throughout the structure and formed tubes through the mold’s rectangular channels, just as they do in the human body.

When brain cells were injected into the surrounding gel, the cells released chemicals that prompted the engineered vessels to sprout new branches, extending the network. A similar system could supply blood to engineered tissue before transplant into the body.

After joining the UW last year, Zheng collaborated with the Puget Sound Blood Center to see how this research platform would work to transport real blood.

The engineered vessels could transport human blood smoothly, even around corners. And when treated with an inflammatory compound the vessels developed clots, similar to what real vessels do when they become inflamed.

The system also shows promise as a model for tumor progression. Cancer begins as a hard tumor but secretes chemicals that cause nearby vessels to bulge and then sprout. Eventually tumor cells use these blood vessels to penetrate the bloodstream and colonize new parts of the body.

When the researchers added to their system a signaling protein for vessel growth that’s overabundant in cancer and other diseases, new blood vessels sprouted from the originals. These new vessels were leaky, just as they are in human cancers.

“With this system we can dissect out each component or we can put them together to look at a complex problem. That’s a nice thing — we can isolate the biophysical, biochemical or cellular components. How do endothelial cells respond to blood flow or to different chemicals, how do the endothelial cells interact with their surroundings, and how do these interactions affect the vessels’ barrier function? We have a lot of degrees of freedom,” Zheng said.

The system could also be used to study malaria, which becomes fatal when diseased blood cells stick to the vessel walls and block small openings, cutting off blood supply to the brain, placenta or other vital organs.

“I think this is a tremendous system for studying how blood clots form on vessels walls, how the vessel responds to shear stress and other mechanical and chemical factors, and for studying the many diseases that affect small blood vessels,” said co-author Dr. José López, a professor of biochemistry and hematology at UW Medicine and chief scientific officer at the Puget Sound Blood Center.

Future work will use the system to further explore blood vessel interactions that involve inflammation and clotting. Zheng is also pursuing tissue engineering as a member of the UW’s Center for Cardiovascular Biology and the Institute for Stem Cell and Regenerative Medicine.

Ref: http://www.sciencedaily.com/releases/2012/05/120528154907.htm

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