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Angiogenesis Developed by the Federation of American Societies for Experimental Biology (FASEB) to educate the general public about the benefits of fundamental biomedical research. INSIDEthis issue Life’s Blood: Angiogenesis in Health and Disease Pumps and Pipes, Frogs and Fish 2 Watching Through Windows 4 Dynamic Plumbing: Angiogenesis and Adaptation 5 Blood and Tumors 6 The Search for Factors: Alphabet Soup 9 Switch Off, Switch On 11 From Finding Factors to Drug Development 12 Into the Clinic and the Headlines 13 Beyond Cancer 15 Promoting Angiogenesis to Save Legs and Lives 15 More to Be Done 17 Acknowledgments Life’s Blood: Angiogenesis in Health and Disease Author, Jacqueline Jaegar Houtman, Ph.D. Scientific Advisors, Robert J. Tomanek, Ph.D., University of Iowa, Carver College of Medicine Joseph C. LaManna, Ph.D., Case Western Reserve University, School of Medicine Scientific Reviewer, Paula Dore-Duffy, Ph.D., Wayne State University, School of Medicine BREAKTHROUGHS IN BIOSCIENCE COMMITTEE James E. Barrett, Ph.D., Chair, Drexel University College of Medicine David Brautigan, Ph.D., University of Virginia, School of Medicine Rao L. Divi, Ph.D., National Cancer Institute, National Institutes of Health Marnie Halpern, Ph.D., Carnegie Institution of Washington Tony T. Hugli, Ph.D., Torrey Pines Institute for Molecular Studies COVER: Angiogenesis, or the formation of new blood ves- sels, plays a critical role in a number of diseases and condi- Mary Lou King, Ph.D., University of Miami School of tions, including cancer, diabetic retinopathy, and wound Medicine healing. Decades of basic research discovery, from studying Fred R. Naider, Ph.D., College of Staten Island, CUNY blood vessels through the thin membrane of a rabbit’s ear Loraine Oman-Ganes, M.D., FRCP(C), CCMG, FACMG, to detailing the mechanism of how human blood vessels are RBC Insurance, Toronto, Canada formed, have contributed to a wide range of modern day therapies, based on increasing or decreasing angiogenesis. Robert N. Taylor, M.D., Emory University School of Images from iStock Photo. Medicine BREAKTHROUGHS IN BIOSCIENCE PRODUCTION STAFF Science Policy Committee Chair: Joseph LaManna, Ph.D., Managing Editor: Carrie D. Wolinetz, Ph.D., Director of Scientific Affairs and Public Relations,, FASEB Office of Public Affairs Production Staff: Lawrence Green, Communications Specialist, FASEB Office of Public Affairs ALife’sN Blood:gIO AngiogenesisgENESIS in Health and Disease Discovery consists of seeing what everybody has seen, and thinking what nobody has thought. Albert Szent-Gyorgi, 1937 recipient of the Nobel Prize in Physiology or Medicine Our cells need oxygen and tissues or, conversely, if blood essary oxygen and nutrients to nutrients to survive. The cells of vessels grow too exuberantly the cells? Decreased blood flow very small organisms can obtain (Table 1). to the legs and feet is a symptom what they need from the envi- What happens when circulation of diabetes or the buildup of ath- ronment by simple diffusion, in is insufficient to provide the nec- erosclerotic plaques in the arter- which nutrients and gases pass from areas of high concentration Diseases related to Diseases related to to low concentration through cell membranes. But diffusion isn’t insufficient angiogenesis excessive angiogenesis very useful over distances greater • Alzheimer’s disease • Cancer than a millimeter or so. Larger • Amyotrophic lateral • Multiple sclerosis animals, including humans, need sclerosis (ALS or Lou • vascular malformations a vascular system, a way for the gehrig’s disease) • Obesity • Diabetes • Psoriasis oxygen and nutrients to get from • Atherosclerosis • Warts the outside environment to every • Hypertension • Allergic dermatitis cell in the body (and for carbon • Crohn’s disease • Kaposi’s sarcoma in AIDS dioxide and waste products to get • Lupus • Diabetic retinopathy back out to the environment). • Preeclampsia • Primary pulmonary • Nephropathy hypertension Cells grow and multiply, and • Chronic wounds • Asthma they die. Their metabolic rates • Coronary artery disease • Cystic fibrosis can change, which changes their • Diabetic ulcers • Inflammatory bowel disease requirements for oxygen and • Periodontal disease nutrients. The vascular system • Liver cirrhosis • Endometriosis can adapt to the body’s changing • Ovarian cysts needs by changing the amount of • Uterine bleeding blood it delivers to the tissues. • Arthritis The formation of new blood ves- • Osteomyelitis sels, a process called angiogen- • Diabetic nephropathy esis, needs to be highly regulated, Table 1 – Examples of diseases related to problems with angiogenesis: The loss of con- and poorly regulated angiogen- trol over angiogenesis (the formation of new blood vessels) can lead to a large number esis can have detrimental effects. of disease states. This is true both when insufficient angiogenesis occurs or when blood vessels grow excessively. Many scientists and physicians believe that understanding and Disease can occur if there are not controlling angiogenesis is a unifying approach to treating a wide variety of diseases. enough blood vessels to feed the Adapted from Carmeliet, P. 2005. Nature 438, 932-936. Breakthroughs in Bioscience 1 ies of the legs. Insufficient blood are leading to new strategies for pump, propelling blood to the supply can result in delayed heal- treating these diseases. But these tissues via the arteries and back ing of wounds as well as pain, breakthroughs have been built on to the heart via the veins, much numbness, or leg weakness, and nearly four centuries of funda- as water is transported through the affected limb may ultimately mental research on angiogenesis, pipes. How the outgoing pipes have to be amputated. as generations of scientists have were connected to the incoming asked the question: how do blood pipes remained a mystery until Decreased blood flow to the vessels grow? 1661, when Marcello Malpighi heart due to atherosclerosis or used the newly invented micro- a clot can damage or kill heart scope to observe tiny capillaries muscle, resulting in symptoms Pumps and Pipes, Frogs connecting the smallest arteries such as angina (chest pain) and and Fish and veins. At around the same shortness of breath. In its most In 1628, William Harvey pro- time, Antony van Leeuwenhoek dire consequence, cellular dam- posed the idea that blood circu- examined the circulatory systems age due to insufficient oxygen lated, with the heart acting as a of tadpoles, fish, rooster combs, may lead to a myocardial infarc- rabbit ears, and bat wings. In a tion, otherwise known as a heart letter, he noted that “the passage attack. Decreased blood flow to a of the blood from the arteries the brain may have similarly dire into the veins of the tadpole, is consequences, including stroke. not performed in any other than On the other hand, what hap- those vessels, which are so min- pens if the formation of blood ute as only to admit the passage vessels is too exuberant? One of a single globule at a time, we consequence is blindness. In the may conclude that the same is U.S., diabetic retinopathy is the B performed in like manner in our leading cause of blindness in own bodies, and in those of other adults of working age, and age- animals.” related macular degeneration is As the quality and power of the leading cause of blindness microscopes increased, blood in elderly adults. Both are the vessels could be observed in result of abnormal growth of greater detail. It wasn’t until late new blood vessels in the eye. c in the 19th century that it was In these neovascular diseases, confirmed that capillaries had the new blood vessels that form walls consisting of a single layer beneath the retina (the back of of cells and a basement mem- the eye, where light is converted, brane (Figure 2). It is through the via electrical/chemical signals, thin walls of the capillaries that to nerve impulses that then go to the exchange of material between the brain) are fragile and often the blood and the tissues occurs. leak, disrupting and damaging Figure 1 – Diabetic retinopathy: Ophthalmoscope views of a normal The vascular endothelial cells the eye tissue, resulting in vision retina (A) and those from patients suf- that make up the walls of the loss (Figure 1). We also now fering from diabetic retinopathy (B, C). capillaries also line the insides of retinopathy, or abnormal angiogenesis know that cancerous tumors are larger vessels and the inner sur- dependent upon angiogenesis for (blood vessel growth) in the retina, is a symptom of diabetes. The retina face of the heart. growth and metastasis (spread- develops an excess of blood vessels (B), ing). which are fragile and leak, causing hem- Techniques for visualizing orrhages (red spots seen in C) that can tissues under the microscope Recent breakthroughs in our lead to blindness. Photo credit: Science continued to advance. By inject- understanding of angiogenesis Photo Library. Breakthroughs in Bioscience 2 Blood Vessel Structure ing dyes or other chemicals into an animal’s circulatory system, Fibrous researchers could trace the circu- outer layer itous routes taken by the smaller blood vessels under the micro- Fibrous outer layer Smooth muscle with scope. Eventually, the electron Smooth muscle elastic fibres with elastic fibres microscope provided even more Lumen Single layer detail. However, even the most of endothelium Lumen sophisticated of these techniques Endothelium Endothelium required tissue to be removed ARTERIES CAPILLARIES VEINS from the animal after death. Figure 2 – Structure of a blood vessel: Arteries, which carry blood away from the heart, By choosing relatively trans- and veins, which return blood to the heart, are connected to each other and other tis- parent tissues as a sort of living sues by very small blood vessels called capillaries. Capillaries are made of single layer of microscope slide, investigators cells, called endothelium (singular = endothelial), and a basement membrane. Figure were able to observe blood cells design by Corporate Press. tumbling in single file through Figure 3 – Single blood cell the capillaries (Figure 3).
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