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Magnetic Resonance Imaging (MRI) enables to provide anatomical, functional and molecular information of pathological angiogenesis when used with properly tailored imaging probes. Functional studies have been the domain of Dynamic Contrast Enhancement (DCE) -MRI protocols from which it is possible to extract quantitative estimations on key parameters such as the volumes of vascular and extracellular compartments and the rates of the bidirectional exchange of the imaging reporters across the endothelial barrier. Whereas paramagnetic Gd-complexes able to reversibly bind to serum albumin act better than the clinically used small-sized, hydrophilic species, new findings suggest that an accurate assessment of the vascular volume is possible by analyzing images acquired upon the i.v. administration of Gd-labelled Red Blood Cells (RBCs). As far as it concerns molecular MRI, among the many available biomarkers, αvβ3 integrins are the most investigated ones. The low expression of these targets makes mandatory the use of nano-sized systems endowed with the proper signal enhancing capabilities. A number of targeted nano-particles have been investigated including micelles, liposomes, iron oxides and perfluorocarbon containing systems. Finally, a growing attention is devoted to the design and testing of "theranostic" agents based on the exploitation of MRI to monitor drug delivery processes and therapeutic outcome.

The endothelium is crucially important for the delivery of oxygen and nutrients throughout the body under homeostatic conditions. However, it also contributes to pathology, including the initiation and perpetuation of inflammation. Understanding the function of endothelial cells (ECs) in inflammatory diseases and molecular mechanisms involved may lead to novel approaches to dampen inflammation and restore homeostasis. In this article, we discuss the various functions of ECs in inflammation with a focus on pathological angiogenesis, attraction of immune cells, antigen presentation, immunoregulatory properties and endothelial-to-mesenchymal transition (EndMT). We also review the current literature on approaches to target these processes in ECs to modulate immune responses and advance anti-inflammatory therapies.

Apelin is the endogenous ligand of the G protein-coupled receptor APJ. Both Apelin and APJ receptor are widely distributed in various tissues such as heart, brain, limbs, retina and liver. Recent research indicates that the Apelin/APJ system plays an important role in pathological angiogenesis which is a progress of new blood branches developing from preexisting vessels via sprouting. In this paper, we review the important role of the Apelin/APJ system in pathological angiogenesis. The Apelin/APJ system promotes angiogenesis in myocardial infarction, ischemic stroke, critical limb ischemia, tumor, retinal angiogenesis diseases, cirrhosis, obesity, diabetes and other related diseases. Furthermore, we illustrate the detailed mechanism of pathological angiogenesis induced by the Apelin/APJ system. In conclusion, the Apelin/APJ system would be a promising therapeutic target for angiogenesis-related diseases.

Liver pathological angiogenesis is considered to be one of the key events in the development of liver fibrosis. Autophagy is a defense and stress regulation mechanism. However, whether autophagy regulates pathological angiogenesis in liver fibrosis is still questionable. Here, we aimed to study how curcumol regulated liver sinusoidal endothelial cells (LSECs) angiogenesis through autophagy. We found that curcumol (10, 20 and 40 μM) could inhibit the expression of angiogenesis markers in the LSECs. Importantly, we showed that curcumol might influence LSEC pathological angiogenesis by regulating autophagy level. Furthermore, we indicated that the transcription factor Krüppel-like factor 5 (KLF5) was considered as a key target for curcumol to regulate LSEC angiogenesis. Interestingly, we also suggested that autophagy was as a potential mechanism for curcumol to restrain KLF5 expression. Increased autophagy level could impair the suppression effect of curcumol on KLF5. Fascinatingly, our results indicated that curcumol inhibited autophagy and led to p62 accumulation, which might be a regulation mechanism of KLF5 degradation. Finally, in mice liver fibrosis model, we unanimously showed that curcumol (30 mg/kg) inhibited pathological angiogenesis by reducing LSEC autophagy level and suppressing KLF5 expression. Collectively, these results provided a deeper insight into the molecular mechanism of curcumol to inhibit LSEC pathological angiogenesis during liver fibrosis.

Angiogenesis is a complex physiological process. However, over the past couple of decades, abnormally accelerated or pathological angiogenesis has garnered greater attention from researchers the world over. Studies have shown that this abnormal and uncontrolled angiogenesis not only promotes inflammatory responses but also plays a role in various malignant and cardiovascular diseases. These include solid tumors, atherosclerosis, blinding retinopathy, and other diseases. Furthermore, there is mounting evidence that noncoding RNAs, especially lncRNAs and microRNAs, play important roles in the regulation of angiogenesis. In recent years, numerous studies have found that lncRNA may serve as an endogenous sponge to regulate the expression and function of miRNA, which in turn bind to lncRNA, regulating their stability. Therefore, this review focuses on the mechanisms of lncRNA/microRNA interactions in angiogenesis. A better understanding of such lncRNA/microRNA interactions may provide helpful insights and shed new light on areas of research for identifying diagnostic markers and therapeutic approaches for treating angiogenesis-related diseases.

Angiogenesis is defined as the growth of new capillaries sprouting from pre-existing vasculature. Pathological angiogenesis signals can lead to dysregulated development of new vessels. Inflammation is accompanied by pathological angiogenesis. During an inflammatory process, newly formed blood vessels provide oxygen and nutrients to the inflamed tissue, facilitating the transport of inflammatory cells. Therefore, angiogenesis is closely related to pathogenesis of inflammatory autoimmune diseases. As a member of the angiopoietin family, Angiopoietin-2 (Ang-2) plays an irreplaceable role in angiogenesis. This review will narrate the expression of Ang-2 and its role in inflammatory autoimmune diseases. Collecting this information may improve the acquaintance of Ang-2 and provide a theoretical foundation for clinical trials and drug development in the future.

For three different types of angiogenesis models with variable delays, we consider either continuous or impulse therapy that eradicates tumor cells and suppresses angiogenesis. For the cancer-free solution, explicit conditions of global stability for the continuous and impulsive systems are obtained, together with delay-dependent estimates for the rates of decay for the tumor volume and pathological angiogenesis.

The extracellular matrix (ECM) is the central element of a pericellular network of bioactive molecules. It orchestrates molecular interactions, availability and activity, acting as a key regulator of cell functions and complex biological processes, including physiological and pathological angiogenesis. The ECM serves as a source of both stimulatory and inhibitory angiogenesis regulatory factors. The observation that several endogenous inhibitors of angiogenesis derive from the ECM proves its importance in physiological angiogenesis, and point to the ECM as a precious source of therapeutic agents for angiogenesis-driven diseases, including cancer growth and metastatic dissemination. This review focuses on the different approaches to exploit ECM molecules for designing tools for therapeutic inhibition or monitoring of pathological angiogenesis, with particular focus on antineoplastic therapy, and emphasis on peptides of ECM moieties and mimetic small molecules.

Summary Identification of cellular surface markers that distinguish tumorous from normal vasculature is important for the development of tumor vessel-targeted therapy. Here, we show that Apj, a G protein-coupled receptor, is highly enriched in tumor endothelial cells but absent from most endothelial cells of adult tissues in homeostasis. By genetic targeting using Apj-CreER and Apj-DTRGFP-Luciferase, we demonstrated that hypoxia-VEGF signaling drives expansion of Apj+ tumor vessels and that targeting of these vessels, genetically and pharmacologically, remarkably inhibits tumor angiogenesis and restricts tumor growth. These in vivo findings implicate Apj+ vessels as a key driver of pathological angiogenesis and identify Apj+ endothelial cells as an important therapeutic target for the anti-angiogenic treatment of tumors.

Selective small molecule inhibitors of Tie-2 kinase are important tools for the validation of Tie-2 signaling in pathological angiogenesis. Reported herein is the optimization of a nonselective scaffold into a potent and highly selective inhibitor of Tie-2 kinase.

To unravel the normal vasculature transcriptome and determine how it is altered by neighbouring malignant cells, we compared gene expression patterns of endothelial cells derived from the blood vessels of eight normal resting tissues, five tumors and regenerating liver. Organ-specific endothelial genes were readily identified, including 27 from brain. We also identified 25 transcripts overexpressed in tumor versus normal endothelium, including 13 that were not found in the angiogenic endothelium of regenerating liver. Most of the shared angiogenesis genes have expected roles in cell cycle control, but those specific for tumor endothelium were primarily cell surface molecules of uncertain function. These studies reveal striking differences between physiological and pathological angiogenesis potentially important for the development of tumor-specific vascular targeted therapies.

The first angiogenesis inhibitors for cancer have now been approved by the F.D.A. in the U.S. and in 28 other countries, including China. The majority of these are monotherapies that block VEGF. However, mutant tumor cells may over time produce redundant angiogenic factors. Therefore, for long-term use in cancer, combinations of angiogenesis inhibitors or broad spectrum angiogenesis inhibitors will be needed. The two most broad spectrum and least toxic angiogenesis inhibitors are Caplostatin and endostatin. Endostatin inhibits 65 different tumor types and modifies 12% of the human genome to downregulate pathological angiogenesis without side-effects. The recent discovery that small increases in circulating endostatin can suppress tumor growth and that orally available small molecules can increase endostatin in the plasma suggests the possible development of a new pharmaceutical field.

s from the 13th Biennial Meeting of the International Society for Applied Cardiovascular Biology September 12–15, 2012 University College, London

The sudden death of Dr. Judah Folkman was tragic, not the least because he had so much left to do. Director of the Vascular Biology Program and former Surgeon-in-Chief at Children's Hospital Boston, he died while en route to address a scientific meeting in Vancouver. His laptop was open on his lap; he had an exhaustive list of investigations underway, all aimed at expanding the diagnostic and therapeutic possibilities of the field he had founded—angiogenesis research.The story of how Judah persevered in the face of skepticism to prove that tumors require a blood supply to grow is legendary. On the long road to establishing angiogenesis as a major field, he always asked the next question, suggested the next experiment, made the unexpected connections of which discovery is born. He brought compassion and wisdom to his roles of healer, scientist, teacher, and mentor. Judah had an extraordinary dedication to his patients day and night.Moses Judah Folkman (Figure 1, Figure 2) was born in Cleveland, Ohio, and grew up in the Midwest. He knew by age 10 that medicine was his calling. The book Dr. Folkman's War, by Robert Cooke, vividly recounts his formative experiences, from visiting hospitalized congregants with his rabbi father to spending hours as a teenager practicing surgical knots and suturing the family's dish towels together, a foreshadowing of the single-minded focus and perseverance that would define his career.Figure 1■■■View Large Image | View Hi-Res Image | Download PowerPoint SlideFigure 2■■■View Large Image | View Hi-Res Image | Download PowerPoint SlideJudah entered Harvard Medical School at 19, served his residency at the Massachusetts General Hospital, and, at 34, was appointed Surgeon-in-Chief at Children's, becoming one of the youngest full professors in Harvard Medical School history. Two pivotal events during Judah's residency years set his future course: he married Paula Prial, with whom he raised the family that rivaled science as his life's love, and he was drafted for a two-year stint in the Navy. While posted at the National Naval Medical Center in Bethesda, Maryland, Judah conducted experiments that stimulated the ideas that would mature into his angiogenesis hypothesis.The scientific community first learned of Judah's angiogenesis theory in 1971, when he published a seminal paper in the New England Journal of Medicine. In it, he proposed that tumors could not grow beyond a certain size without a dedicated blood supply. He postulated that they secreted a protein to stimulate the ingrowth of capillaries, and that this process, angiogenesis, transformed a tumor composed of mutated but harmless cells into a potentially lethal neoplasm. Since physiological processes most often have checks and balances, he further proposed that naturally occurring substances that inhibited angiogenesis kept some tumors dormant despite their malignant potential.The decade that followed was a challenging period spent identifying the molecular basis of tumor angiogenesis. Toward this end, Judah developed the assays and tools to study angiogenesis in vivo and in vitro. These assays remain in use today. They include long-term culture of capillary endothelial cells, the chick chorioallantoic membrane and corneal pocket bioassays, and the sustained-release polymers required to deliver angiogenic regulators to be tested.In the early 1980s, the lab purified the first angiogenic stimulator, basic fibroblast growth factor (bFGF), which ushered in an era of discovery, validation, and refinement that established angiogenesis as the defining process in a tumor's ability to grow and metastasize. In the decades since, Judah's lab and others have identified more than 30 endogenous angiogenesis inhibitors, including angiostatin and endostatin, and over a dozen stimulators, and they have begun mapping multiple pathways through which pathological angiogenesis occurs. Drugs based on these discoveries are now benefiting more than 1.2 million people worldwide. Ten are approved in the US and other countries for cancer and the wet form of age-related macular degeneration (ARMD), which is also angiogenesis dependent; another 40-plus are in clinical trials. The ARMD drugs are the first ever to reverse blindness.Judah was gratified but not satisfied with these advances. As always, his vision was bigger. In 1989, he proposed the concept of the “angiogenic switch,” the point in a tumor's development when the balance of stimulators and inhibitors is altered in favor of angiogenesis stimulation, triggering the transition to the angiogenic phenotype. He theorized that blocking the switch would keep cancer from developing. The key would be to identify biomarkers of the switch, then “treat the biomarker” with nontoxic angiogenesis inhibitors, akin to using statins in response to high cholesterol levels. He had begun clinical trials to evaluate the efficacy of biomarkers in detecting recurrent cancer before the tumors could be imaged or palpated, a first step toward his vision of “cancer without disease.”His vision for angiogenic therapies did not stop there, however. He viewed angiogenesis as an organizing principle of biology and pathological angiogenesis as a common factor in many disparate diseases. He pointed out that angiogenesis is necessary to support the growth of any mass—be it an arthrosclerotic plaque, adipose tissue, or a malignancy, and that it characterizes conditions as different as retinopathies and endometriosis. This shared characteristic led Judah to propose that angiogenesis-based biomarkers could be used to monitor the progression or regression of a number of these diseases. Further, drugs developed for one angiogenesis-dependent disorder could potentially treat another. This had already happened with Avastin, the cancer drug some ophthalmologists used to successfully treat wet ARMD before the more targeted eye drugs Lucentis and Macugen received approval. Judah envisioned a time when a single, broad-spectrum angiogenesis inhibitor or a combination of antiangiogenic drugs would be used to treat a wide range of conditions.Judah Folkman authored some 400 peer-reviewed papers and more than 100 book chapters and monographs. He had been elected to the National Academy of Sciences, the American Academy of Arts and Sciences, the American Philosophical Society, the Institute of Medicine, and the President's Cancer Advisory Board. The research lab he founded with a single assistant when he came to Children's Hospital Boston in 1967 had, by the time of his death, grown into a 100-scientist-strong Vascular Biology Program. More than 1000 labs around the world are now pursuing angiogenesis research, yielding thousands of angiogenesis-related publications each year.That the challenge Judah Folkman faced in 1971 had been met was nowhere more apparent than in the awards and honorary degrees crowding every inch of the walls of one of the Vascular Biology Program's conference rooms. But the display in a second conference room was even more meaningful to him. There, the walls exhibit journal covers reflecting the achievements of all 13 of the Vascular Biology Program's labs, many of which are now run by scientists who began their careers as Folkman post-docs. Judah was intensely proud of his scientific progeny.Judah Folkman's fiercely original and courageous intelligence, his gift for focusing on big, important questions that could make a difference in people's lives, and his delight in discovery inspired hundreds of scientists, clinicians, and patients all over the world. We are honored and grateful to have been witness to his genius and his selflessness.

International audience

Confocal Endomicroscopy and Molecular Imaging Demonstrates in Colonic Mucosa of Patients With IBD in Remission Impaired Crypt Regeneration, Persistant Inflammation and Pathological Angiogenesis. Underlying Mechanisms Include Dysregulation of Survivin and Aberrant Activation of VEGF Gene. Andrzej S. Tarnawski, Emmanuel Coron, Zsuzsa Sandor, Jean-Francois Mosnier, Amrita Ahluwalia, Marc Le Rhun, Jean-Paul Galmiche, Tamara Matysiak-Budnik

Bone marrow-derived cells have been recently proposed to participate in the development of new blood vessels during physiological and pathological angiogenesis in adult organisms.