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Cell Adhesion and Angiogenesis Cell adhesion and angiogenesis. J Bischoff J Clin Invest. 1997;99(3):373-376. https://doi.org/10.1172/JCI119168. Perspective Find the latest version: https://jci.me/119168/pdf Perspectives Series: Cell Adhesion in Vascular Biology Cell Adhesion and Angiogenesis Joyce Bischoff Department of Surgery, Children’s Hospital and Harvard Medical School, Children’s Hospital, Boston, Massachusetts 02115 Introduction and postcapillary venules (3). Thus, the formation of a new mi- Angiogenesis is the growth of new capillary blood vessels from crovessel requires a number of interactions that must be coor- preexisting capillaries and postcapillary venules. This process dinated in a spatially and temporally specified manner. These is critical for normal growth and development and in protec- adhesion events are likely mediated by endothelial cell adhe- tive responses such as wound healing and inflammation. In sion molecules and ECM molecules that provide instructions healthy adults, angiogenesis does not normally occur except in to the endothelial cells as they migrate into the perivascular certain phases of the female reproductive cycle. However, ab- space and assemble into new vessels with surrounding peri- errant angiogenesis can occur in a variety of pathologic set- cytes. tings. These include the neovascularization of solid tumors, the Cell adhesion and endothelial cell growth growth of vessels into the retina in diabetic retinopathy, and the unwanted vessel growth in chronic inflammatory diseases. Adhesion of endothelial cells to ECM and attainment of an The hypothesis that angiogenic diseases, in particular tumor appropriate cellular shape has been known for many years to growth and metastases, may be alleviated by inhibiting the an- be crucial for endothelial cell growth, differentiation, and sur- giogenic responses (1) has prompted many to investigate the vival. In 1978, Folkman and Moscona used poly(2-hydroxy- basic mechanisms by which endothelial cells are stimulated to ethyl methacrylate) to vary the adhesiveness of plastic culture undergo angiogenesis. The goal is to identify biochemical dishes in order to measure the effect of cell adhesion and events that constitute potential targets for antiangiogenic ther- shape on proliferation of bovine aortic endothelial cells (4). In- apy (2). A recent strategy has been to identify endogenous an- creased cell spreading, determined by measuring cell diameter giogenesis inhibitors and use these molecules to control angio- and height, was found to be tightly coupled to increased 3 genesis. [ H]thymidine incorporation and cellular proliferation. Thus, Endothelial cell proliferation is a major component of an- the shape of the cells, and not just attachment of cells to the giogenesis, but is only one of a series of tasks the endothelial substratum, is a critical parameter for growth. Similar results cells must accomplish to form a new capillary blood vessel. In were obtained when varying densities of fibronectin were used response to angiogenic stimuli, endothelial cells degrade the to modulate shape of bovine capillary endothelial cells in se- extracellular matrix (ECM),1 migrate into the perivascular rum-free conditions (5). In subsequent studies, nonadherent space, proliferate, and align themselves into patent blood ves- endothelial cells in suspension were found to undergo pro- sels. When sufficient angiogenesis has occurred, the endothe- grammed cell death (6). The programmed cell death (i.e., apop- lial cells become quiescent and the vessels either remain or re- tosis) could be prevented by plating the endothelial cells on fi- gress if no longer needed. During these events, the endothelial bronectin-coated or anti–␤1 integrin-coated dishes but not cells must adhere to one another and to the ECM to construct dishes coated with anti–vascular cell adhesion molecule-1 anti- and extend new microvessels. The endothelial cells also form bodies. These studies indicate that integrin binding to ECM branches which then connect to other branches to form capil- ligands plays a crucial role in endothelial cell growth and sur- lary loops. The polarity of the endothelial cell, luminal versus vival. The consequences of disrupting requisite adhesion events abluminal, must also be established. Pericytes, which are may be twofold. Endothelial cells in a sprouting vessel may be- thought to regulate function and growth, are found associated come misguided and unable to assemble into a new capillary with the abluminal surfaces of mature capillary blood vessels blood vessel and/or the cells may undergo programmed cell death in response to the lack of appropriate cell contacts. The mechanism(s) by which the extracellular environment affects Address correspondence to Joyce Bischoff, Ph.D., Children’s Hospi- endothelial cell adhesion, shape, and proliferation is a central tal, 300 Longwood Ave., Boston, MA 02115. Phone: 617-355-7865; question in angiogenesis research. FAX: 617-355-7043; E-mail: [email protected] Received for publication 22 December 1996. Endothelial cell adhesion molecules To date, four families of cell adhesion molecules have been de- 1. Abbreviations used in this paper: CAM, chorioallantoic membrane; scribed: integrins, immunoglobulin superfamily members, cad- ECM, extracellular matrix. herins, and selectins. Members of each family have been de- tected in angiogenic blood vessels. The integrin family of J. Clin. Invest. heterodimeric adhesion molecules functions in a variety of © The American Society for Clinical Investigation, Inc. cell–matrix and cell–cell interactions in the vasculature. Sev- 0021-9738/97/02/0373/04 $2.00 eral integrins are expressed on luminal and abluminal surfaces Volume 99, Number 3, February 1997, 373–376 of endothelial cells and have been shown to participate in en- Cell Adhesion and Angiogenesis 373 dothelial cell migration and formation of capillary-like tubes in The mechanism by which anti-␣v␤3 mAb disrupts angio- vitro (7). In vivo, integrins have been shown to be involved in genesis appears to involve apoptosis since LM609-positive both angiogenesis and vasculogenesis. One particular com- blood vessels were found colocalized with apoptotic cells (11). plex, the ␣v␤3 integrin, has been studied extensively in a num- This finding suggests that proper ligation of ␣v␤3 to its endog- ber of in vivo models in which angiogenesis can be induced. enous ligand is important for maintaining the appropriate ␣v␤3 is detected in growing but not quiescent blood vessels angiogenic signal to endothelial cells. In the absence of such and is also expressed on a number of other cell types including signals, proliferating endothelial cells respond by initiating tumor cells, smooth muscle cells, fibroblasts, and leukocytes. programmed cell death. In support of this, disruption of ␣v␤3 Furthermore, ␣v␤3 can bind an array of ligands such as vi- binding in proliferating endothelial cells was found to result in tronectin, fibronectin, von Willebrand factor, fibrinogen, os- expression of conflicting cellular signals in that p53 activity and teopontin, thrombospondin, and RGD-containing peptides. cell cycle inhibitor p21waf1/cip1 were induced (15). (p53 expres- Recently, ␣v␤3 integrin expressed on lymphokine-activated sion in proliferating cells has been shown to trigger apoptosis.) killer cells has been shown to bind PECAM-1/CD31 (8) and Interestingly, attachment of human umbilical vein endothelial ␣v␤3 expressed on melanoma cells has been shown to bind cells to the LM609 mAb immobilized on tissue culture dishes matrix metalloproteinase-2 (9), despite the lack of RGD se- rescued cells from expression of p53 activity and p21waf1/cip1. quences in these two polypeptides. Thus, ␣v␤3 can be expressed Thus, the same antibody that exerts dramatic antiangiogenic in many cell types and may bind to a diverse array of ligands in effects in vivo can prevent expression of growth inhibitory ac- many settings, including but not limited to angiogenesis. tivities in vitro. This suggests that cell attachment via ␣v␤3 is The importance of ␣v␤ integrins in angiogenesis was first required for maintaining an angiogenic program in endothelial elucidated by Cheresh and colleagues in a series of experi- cells. It would be of interest to analyze endothelial cells plated ments (10, 11) using an anti-␣v␤3 mAb designated LM609 and on poly(2-hydroxyethyl methacrylate) or fibronectin, as de- a cyclic RGD-peptide antagonist of ␣v-integrins. The LM609 scribed in early studies (4, 5), to determine the pattern of p53 mAb has proved to be a valuable and essential reagent for and p21waf1/cip1 expression in spread versus round endothelial their investigations in that LM609 reacts with several species cells. including human, chick, quail, and rabbit ␣v␤3 integrins, it is An important question is whether loss of cell adhesion, ei- highly specific for the heterodimeric complex, and it can react ther to matrix or adjacent cells, is a critical step by which an- with the complex in a variety of experimental conditions. giogenesis is switched off and vessel regression ensues, in ei- In the chick chorioallantoic membrane (CAM) assay, an in ther normal development or in pathological angiogenesis. vivo assay for angiogenesis, LM609 mAb inhibited blood ves- Signals that trigger apoptosis, whether due to loss of cell con- sel growth induced by implanting an ␣v␤3-negative melanoma tact, as shown with ␣v␤3, or loss of an angiogenic factor, are or induced by implanting a pellet containing basic fibroblast likely to be important
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