The New Angiotherapy EDITED BY Tai-Ping D. Fan, PhD Elise C. Kohn, MD Humana Press THE NEW ANGIOTHERAPY THE NEW ANGIOTHERAPY HUMANA PRESS TOTOWA, NEW JERSEY Edited by TAI-PING D. FAN, PhD University of Cambridge, UK and ELISE C. KOHN, MD National Institutes of Health, Bethesda, MD Foreword by J UDAH FOLKMAN, MD Department of Surgery, Children’s Hospital, Harvard Medical School, Boston, MA © 2002 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 humanapress.com For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel: 973-256-1699; Fax: 973-256-8341; E-mail: humana@humanapr.com or visit our Website at http://humanapress.com All rights reserved. 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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data The new angiotherapy/edited by Tai-Ping Fan and Elise C. Kohn p.; cm. Includes bibliographical references and index. ISBN 0-89603-464-X (alk. paper) 1. Neovascularization. 2. Neovascularization inhibitors. I. Fan, Tai-Ping D. II. Kohn, Elise C. [DNLM: 1. Neovascularization, Pathologic. 2. Neovascularization, Physiologic. WG 500 N5324 2001] QP106.6 .N49 2001 612.1'3—dc21 00-050029 DEDICATION To Dorothy, our two children, Victoria and Patrick, as a token of my love and apprecia- tion for their immense patience and many sacrifices in making my dreams come true. Also to my grandmother, parents, and brothers and sisters for their constant encouragement TPF To my husband, Gary Claxton, for his loving support, to my mentor, Dr. Lance Liotta, for his valuable advice and encouragement, and to very dear friends without whom this book could not have been finished ECK v [...]... primary capillary plexus The existence of the angioblast, which differentiates exclusively into endothelial cells, has been well-established However, definitive proof for the existence of the hemangioblast, which is purported to have the dual capacity to differentiate into either endothelial or hematopoietic cells, is still lacking (reviewed in refs 1–4) From: The New Angiotherapy Edited by: T.-P D... negative regulators is called into play Furthermore, it is at present unclear as to whether the resolution phase is an active phase, or whether it is the consequence of exhaustion of positive regulators that predominated during the phase of activation If the latter hypothesis is correct, this assumes that endothelial cells have the inherent capacity to synthesize their own basement membrane and to organize... parameters: first, by the presence and concentration of other cytokines in the pericellular environment of the responding cell; second, by interactions between cells, cytokines, and the extracellular matrix; and third, by the geometric configuration of the cells (and thus their cytoskeleton) With respect to angiogenesis, the molecular mechanisms underlying the notions of both the “angiogenic switch”... vivo, the current working hypothesis is that the “switch” involves either the induction of a positive regulator and/or the loss of a negative regulator With respect to activated endothelium, an important distinction needs to be made between physiological and pathological settings: although many of the same positive and negative regulators are operative in both, endothelial-cell proliferation in the former... from the notion that for tumors to grow beyond a critical size, they must recruit endothelial cells from the surrounding stroma to form their own endogenous microcirculation (reviewed in ref 10) Thus during tumor progression, two phases can be recognized: a prevascular phase and a vascular phase The transition from the prevascular to the vascular phase is referred to as the “angiogenic switch.” The. .. as their capacity for histotypic morphogenesis, i.e., the formation of capillary-like tubes The model consists of cultivating endothelial cells on the surface of three-dimensional collagen (16) or fibrin (17) gels; under these conditions, the cells form a monolayer on the surface of the gel and do not invade the underlying matrix (Fig 3A) When the monolayer is treated with an angiogenic factor such... occurs in the lymphatic system, and is sometimes referred to as lymphangiogenesis Evidence has recently been provided for the existence, in the peripheral circulation, of an endothelial-cell precursor that contributes to the formation of new blood vessels in postnatal life (6) These findings are likely to have a major impact on the current definition of angiogenesis Recall that although the formation... smooth-muscle cells) Furthermore, capillaries in many organs undergo further differentiation and develop organ-specific functions Examples include formation of the blood-brain barrier (BBB) in the central nervous system (CNS), formation of fenestrated endothelium in endocrine and other organs, formation of sinusoids in the liver and spleen, and formation of high endothelial venules in lymph nodes These processes,... well as the organization of these endothelial cells into capillary-like tubes With respect to the phases of activation and resolution, many components are equally as applicable to vasculogenesis as they are to angiogenesis Although a great deal is known about those factors that induce the activation phase, very little is known about the factors involved in the phase of resolution, in which the dominant... development and thereby missing important aspects of angiotherapy Foremost is the idea that vasculogenesis and angiogenesis are mutually exclusive This idea is simply wrong As we have pointed out previously (11) blood-vessel development in the metanephros involves both angiogenesis and vasculogenesis Still, these are embryonic rudiments, and therefore do not answer the important question of whether vasculogenesis . The New Angiotherapy EDITED BY Tai-Ping D. Fan, PhD Elise C. Kohn, MD Humana Press THE NEW ANGIOTHERAPY THE NEW ANGIOTHERAPY HUMANA PRESS TOTOWA, NEW JERSEY Edited by TAI-PING. Kohn have assembled, in The New Angiotherapy, chapters written by many of the leading scientists in the field of angiogenesis research. The molecular underpinnings of the angiogenic process in. to recognize the emergence of unifying themes in the study of angiogenesis. The growth of new microvessels from resting vessels is the outcome of a fine balance between molecules that are either positive