Showing papers on "Vascular endothelial growth factor A published in 1987"

Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix

Abstract: Bovine aortic and corneal endothelial cells synthesize a growth factor that remains mostly cell-associated but can also be extracted from the subendothelial extracellular matrix (ECM) deposited by these cells. The endothelial cell-derived growth factors extracted from cell lysates and from the extracellular matrix appear to be structurally related to basic fibroblast growth factor by the criteria that they bind to heparin-Sepharose and are eluted at 1.4-1.6 M NaCl, have a molecular weight of about 18,400, cross-react with anti-basic fibroblast growth factor antibodies when analyzed by electrophoretic blotting and immunoprecipitation, and are potent mitogens for bovine aortic and capillary endothelial cells. It is suggested that endothelium can store growth factors capable of autocrine growth promotion in two ways: by sequestering growth factor within the cell and by incorporating it into the underlying extracellular matrix.

Capillary endothelial cells express basic fibroblast growth factor, a mitogen that promotes their own growth

Abstract: Angiogenesis, the formation of new capillaries, which is observed in embryonic and injured tissue and is particularly prominent in the vicinity of solid tumours1, involves the migration and proliferation of capillary endothelial cells. It is probably triggered by agents, such as basic fibroblast growth factor (bFGF), thought to be released from tissues adjacent to proliferating capillaries1. As well as being a potent inducer of cell division in capillary endothelial cells in vitro, bFGF can act as an angiogenic agent in vivo2. It is present in a wide variety of richly vascularized tissues including brain, pituitary, retina, adrenal gland, kidney, corpus luteum, placenta and various tumours1–3. So far, however, the normal bFGF-producing cell species in these tissues have not been identified2,4. We report here that capillary endothelial cells express the bFGF gene, that they produce and release bFGF and that bFGF derived from them can stimulate the proliferation of capillary endothelial cells. We conclude that bFGF can act as a self-stimulating growth factor for capillary endothelial cells, and that it is possible that the formation of new capillaries is induced by capillary endothelial cells themselves.

Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo.

Abstract: Tumor necrosis factor type alpha (TNF-alpha) inhibits endothelial cell proliferation in vitro. Basal cell growth (in the absence of exogenously added growth factor) and fibroblast growth factor (FGF)-stimulated cell proliferation are inhibited in a dose-dependent manner from 0.1 to 10 ng/ml with half-maximal inhibition occurring at 0.5-1.0 ng of TNF-alpha per ml. Bovine aortic and brain capillary endothelial and smooth muscle cells are similarly affected. TNF-alpha is a noncompetitive antagonist of FGF-stimulated cell proliferation. Its action on endothelial cells is reversible and noncytotoxic. Surprisingly, TNF-alpha does not seem to inhibit endothelial cell proliferation in vivo. In the rabbit cornea, even a high dose of TNF-alpha (10 micrograms) does not suppress angiogenesis induced by basic FGF. On the contrary, in this model system TNF-alpha stimulates neovascularization. The inflammatory response that is seen in the cornea after TNF-alpha implantation suggests that the angiogenic properties of this agent may be a consequence of leukocyte infiltration.

Inhibitory action of transforming growth factor beta on endothelial cells

Abstract: In the present study, we show that transforming growth factor beta (TGF-beta) strongly inhibits fibroblast growth factor-induced proliferation and motility of bovine endothelial cells in tissue culture. TGF-beta also prevents the phorbol ester-induced invasion of capillary endothelial cells into collagen matrices--i.e., blocks angiogenesis in vitro. TGF-beta promotes the incorporation of fibronectin into the extracellular matrix of endothelial cells and stimulates the secretion of other proteins--mainly of 55- and 180-kDa components. We show furthermore that endothelial cells express TGF-beta receptors similar in size to those of other tissue culture cell lines: a 280-kDa complex is present in subconfluent cells, and 85- and 72-kDa protein bands are seen in confluent cells. The various effects of TGF-beta on endothelial cells suggest that these cells are an important target of TGF-beta during wound healing and angiogenesis.

Inhibition of Endothelial Cell Proliferation by Gamma-Interferon

Abstract: Endothelial cell growth factor (ECGF) is a potent polypeptide mitogen for endothelial cells and fibroblasts. The mitogenic effects of ECGF are inhibited by the lymphokine gamma-interferon (gamma-IFN) in a dose-dependent manner. Gamma-IFN also induces a unique change in endothelial cell morphology which is maximally expressed in the presence of ECGF. The antiproliferative and phenotypic modulatory effects of gamma-IFN on endothelial cells are reversible. Inhibition of ECGF-induced endothelial cell proliferation by gamma-IFN is accompanied by a concentration- and time-dependent decrease in binding of 125I-ECGF to the endothelial cell surface. Scatchard analyses of the binding data in the presence and absence of gamma-IFN demonstrate a decrease in the number of ECGF-binding sites rather than a decrease in ligand affinity for the receptor. Cross-linking experiments with disuccinimidyl suberate demonstrate a decrease in the 170,000 Mr cross-linked receptor-ligand complex. These data suggest that gamma-IFN inhibits endothelial cell proliferation by a mechanism which involves growth factor receptor modulation.

Interleukin 1 stimulates human endothelial cells to produce granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor.

Abstract: Endothelial cells are a potent source of hematopoietic growth factors when stimulated by soluble products of monocytes. Interleukin 1 (IL 1) is released by activated monocytes and is a mediator of the inflammatory response. We determined whether purified recombinant human IL 1 could stimulate cultured human umbilical vein endothelial cells to release hematopoietic growth factors. As little as 1 U/ml of IL 1 stimulated growth factor production by the endothelial cells, and increasing amounts of IL 1 enhanced growth factor production in a dose-dependent manner. Growth factor production increased within 2 to 4 hr and remained elevated for more than 48 hr. To investigate the molecular basis for these findings, oligonucleotide probes for granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and multi-CSF were hybridized to poly(A)-containing RNA prepared from unstimulated and IL 1-stimulated endothelial cells. Significant levels of GM-CSF and G-CSF, but not M-CSF or multi-CSF, mRNA were detected in the IL 1-stimulated endothelial cells. Biological assays performed on the IL 1-stimulated endothelial cell-conditioned medium confirmed the presence of both GM- and G-CSF. These results demonstrate that human recombinant IL 1 can stimulate endothelial cells to release GM-CSF and G-CSF, and provide a mechanism by which IL 1 could modulate both granulocyte production and function during the course of an inflammatory response.

Aortic endothelial cells synthesize basic fibroblast growth factor which remains cell associated and platelet-derived growth factor-like protein which is secreted.

Abstract: Cultured bovine aortic endothelial cells synthesize growth factors which markedly differ in the regulation of their storage and secretion. Endothelial cell lysates, but not conditioned medium, contain a growth factor activity that appears to be basic fibroblast growth factor (FGF) by the following criteria: (1) it elutes from heparin-Sepharose at 1.4–1.6 M NaCl; (2) it is mitogenic for bovine aortic and capillary endothelial cells; (3) it is heat sensitive but stable to dithiothreitol; (4) it has a molecular weight of about 18,000 daltons; and (5) it cross-reacts with antiserum directed against basic FGF. In contrast, endothelial cell conditioned medium, but not lysates, contains a growth factor activity that (1) elutes from heparin-Sepharose at 0.4 – 0.5 M NaCl; (2) is mitogenic for fibroblasts and vascular smooth muscle cells but not for capillary endothelial cells; (3) is heat stable and dithiothreitol sensitive; and (4) competes with platelet-derived growth factor (PDGF) for binding to fibroblasts. From these criteria, it appears that endothelial cells secrete into the medium growth factors some of which are PDGF-like, but secrete little if any basic FGF. It is suggested that endothelial cell-associated basic FGF acts in an autocrine fashion to stimulate endothelial cell proliferation in response to endothelial cell perturbation or injury. On the other hand, the endothelial cell-secreted growth factors which are smooth muscle cell but not endothelial cell mitogens might exert a paracrine function on neighboring cells of the vessel wall.

Interleukin 1 induces cultured human endothelial cell production of granulocyte-macrophage colony-stimulating factor.

Abstract: Monokine-stimulated endothelial cells are known to produce both burst- and colony-stimulating activities, but neither the nature of the monokine nor the hematopoietic growth factor(s) produced is known. We show by mRNA analysis that an immortalized line of human endothelial cells constitutively produce granulocyte-macrophage colony-stimulating factor. Furthermore, interleukin 1 and tumor necrosis factor induce early passage human umbilical endothelial cells to produce the same growth factor.

Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor).

Abstract: The control of vascular endothelial and smooth muscle cell proliferation is important in such processes as tumor angiogenesis, wound healing, and the pathogenesis of atherosclerosis. Class I heparin-binding growth factor (HBGF-I) is a potent mitogen and chemoattractant for human endothelial cells in vitro and will induce angiogenesis in vivo. RNA gel blot hybridization experiments demonstrate that cultured human vascular smooth muscle cells, but not human umbilical vein endothelial cells, express HBGF-I mRNA. Smooth muscle cells also synthesize an HBGF-I-like polypeptide since (i) extract prepared from smooth muscle cells will compete with 125I-labeled HBGF-I for binding to the HBGF-I cell surface receptor, and (ii) the competing ligand is eluted from heparin-Sepharose affinity resin at a NaCl concentration similar to that required by purified bovine brain HBGF-I and stimulates endothelial cell proliferation in vitro. Furthermore, like endothelial cells, smooth muscle cells possess cell-surface-associated HBGF-I receptors and respond to HBGF-I as a mitogen. These results indicate the potential for an additional autocrine component of vascular smooth muscle cell growth control and establish a vessel wall source of HBGF-I for endothelial cell division in vivo.

An angiogenic growth factor is expressed in human glioma cells.

Abstract: Progression to increased malignancy frequently occurs in human brain tumors of glial origin and usually involves neovascularization--a massive proliferation of endothelial cells into the tumor tissue. We have shown previously that subversion of a normal growth factor-related pathway is frequently associated with human gliomas. Here we show that human glioma cell lines express the gene encoding the angiogenic peptide endothelial cell growth factor (ECGF) or acidic fibroblast growth factor (a-FGF) and that an ECGF-like polypeptide is produced by these cells. The glioma-derived growth factor was partially purified from cell extracts by heparin-Sepharose affinity chromatography where it eluted at 1.5 M sodium chloride. On reversed-phase h.p.l.c., growth factor activity for endothelial cells was eluted at the same concentration of acetonitrile as found for bovine brain-ECGF, also a potent mitogen for endothelial cells. Moreover, human glioma cells possess specific cell surface receptors for ECGF and are mitogenically stimulated by exogenous addition of this growth factor. Glioma derived-ECGF may therefore have a dual influence: first, by autocrine growth-stimulation of human gliomas and, second, by paracrine-stimulation of endothelial cell proliferation which results in neovascularization of the tumor tissue.

Growth inhibition by protein kinase C late in mitogenesis.

Abstract: The importance of α-thrombin in the clotting cascade is well-known, but it is also a potent mitogen1–3 Like many other mitogens, thrombin causes receptor-mediated activation of a phosphatidy-linositol-specific phospholipase C (PLC), leading to the release of diacylglycerol and the subsequent activation of protein kinase C (refs 3–6) Protein kinase C is probably important in cell proliferation, as activation of this enzyme by phorbol esters promotes growth in many systems4–6 Some growth factors have tyrosine kinase activity and function without activation of PLC or protein kinase C7–9 In this report we show that α-thrombin retains its mitogenicity in vascular smooth muscle cells depleted of protein kinase C Phorbol-12-myristate-13-acetate (PMA) is found to be a potent growth inhibitor when added to vascular smooth muscle cells with α-thrombin Moreover, growth inhibition is maximal when protein kinase C is activated 4 hours after exposure to thrombin, long after the completion of 'early events' induced by thrombin Thus, PMA probes an event late in the G1 phase of the cell cyle or at the G1–S transition

Effects of tumour necrosis factor and related cytokines on vascular endothelial cells.

Abstract: Tumour necrosis factor (TNF) and related cytokines have been found to alter the phenotype of vascular endothelial cells so as to promote coagulation, inflammation and immunity. We have used recombinant human TNF, lymphotoxin (LT), interleukin 1 alpha (IL-1 alpha) and interleukin 1 beta (IL-1 beta) to study and compare the effects of these molecules on cultured human endothelial cells (HEC). All four mediators cause HEC monolayers to reorganize from an epithelioid to a fibroblastoid morphology. Reorganization is slow (days), reversible upon cytokine withdrawal and enhanced by co-addition of immune interferon. Coincident with morphological change, TNF and LT (but not IL-1 alpha or IL-1 beta) cause a marked increase in HLA-A, B mRNA and antigen expression. TNF and LT also induce a slow increase in the mRNA levels and cell-surface expression of IL-1 species. All four cytokines have been reported to enhance HEC adhesiveness for lymphocytes and inflammatory leucocytes; these changes temporally coincide with a rapid (hours) and sustained increase in expression of intercellular adhesion molecule 1 (ICAM-1), and with a rapid but transient de novo expression of an endothelial-leucocyte adhesion molecule (detected by antibody H4/18), respectively. TNF and LT induce reciprocal tachyphylaxis for the reinduction of H4/18 binding but do not inhibit induction by IL-1 alpha and IL-1 beta; similarly, IL-1 alpha and IL-1 beta induce reciprocal tachyphylaxis but do not inhibit TNF or LT. We have used the binding of H4/18 to explore the mechanism of action of TNF. Tumour-promoting phorbol esters, but not agents which increase cytoplasmic calcium concentrations, were found to induce binding, suggesting a possible involvement of the protein kinase C pathway in the response of HEC to TNF. Cells pretreated for 24 hours with phorbol esters cannot be reinduced to express H4/18 binding by phorbol esters yet retain full responsiveness to TNF. Thus TNF also appears to act on HEC through a pathway independent of protein kinase C activation. Collectively, these effects of TNF and related cytokines may be understood as examples of endothelial cell activation.

Protein kinase C activators suppress stimulation of capillary endothelial cell growth by angiogenic endothelial mitogens.

Abstract: The intracellular events regulating endothelial cell proliferation and organization into formalized capillaries are not known. We report that the protein kinase C activator beta-phorbol 12,13-dibutyrate (PDBu) suppresses bovine capillary endothelial (BCE) cell proliferation (K50 = 6 +/- 4 nM) and DNA synthesis in response to human hepatoma-derived growth factor, an angiogenic endothelial mitogen. In contrast, PDBu has no effect on the proliferation of bovine aortic endothelial cells and is mitogenic for bovine aortic smooth muscle and BALB/c 3T3 cells. Several observations indicate that the inhibition of human hepatoma-derived growth factor-stimulated BCE cell growth by PDBu is mediated through protein kinase C. Different phorbol compounds inhibit BCE cell growth according to their potencies as protein kinase C activators (12-O-tetradecanoylphorbol 13-acetate greater than PDBu much greater than beta-phorbol 12,13-diacetate much much greater than beta-phorbol; alpha-phorbol 12,13-dibutyrate; alpha-phorbol 12,13-didecanoate). PDBu binds to a single class of specific, saturable sites on the BCE cell with an apparent Kd of 8 nM, in agreement with reported affinities of PDBu for protein kinase C in other systems. Specific binding of PDBu to BCE cells is displaced by sn-1,2-dioctanoylglycerol, a protein kinase C activator and an analog of the putative second messenger activating this kinase in vivo. The weak protein kinase C activator, sn-1,2-dibutyrylglycerol, does not affect PDBu binding. A cytosolic extract from BCE cells contains a calcium/phosphatidylserine-dependent protein kinase that is activated by sn-1,2-dioctanoylglycerol and PDBu, but not by beta-phorbol. These findings indicate that protein kinase C activation can cause capillary endothelial cells to become desensitized to angiogenic endothelial mitogens. This intracellular regulatory mechanism might be invoked during certain phases of angiogenesis, for example when proliferating endothelial cells become differentiated to organize into nongrowing tubes.

Polarized Secretion of a Platelet-derived Growth Factor-like Chemotactic Factor by Endothelial Cells In Vitro

Abstract: Cultured bovine aortic endothelial cells secrete a potent migration-stimulating factor for vascular smooth muscle cells (SMCs) and adventitial fibroblasts. Vascular pericytes are 20-fold less responsive, and endothelial cells themselves do not respond at all. Checkerboard analysis of SMC migration in a micro-chemotaxis chamber assay shows that the factor is chemotactic. Chemotactic activity for SMCs and adventitial fibroblasts is specifically inhibited by antibodies against platelet-derived growth factor. Endothelial cells cultured on nitrocellulose filters secrete the platelet-derived growth factor-like factor almost exclusively into the basal compartment. We suggest that this factor plays an important role in the recruitment of vascular wall cells during the morphogenesis of blood vessels and pathological conditions, such as atherosclerosis.

Activation of endothelial cells.

Abstract: The disposition of blood in contact with natural or artificial surfaces is the outcome of interactions between the components of blood with specific recognition sites on the endothelium or lack of such specific signaling. Endothelial cells of all vascular beds provide a dynamic interface for interaction with substrates and formed elements arriving via the blood and for interaction with the underlying layers of the vascular wall.' We will focus particularly on pulmonary endothelium since pulmonary endothelial cells are strategically situated both for regulation of the quality of systemic arterial blood and for transduction of blood-borne signals that may affect vascular tone.* However, it is the same anatomic location that makes pulmonary endothelium an immediate target of vascular injury in a wide range of conditions. Thus, it may be appropriate to consider some of the interactions between blood-borne cells and molecules with the endothelial surface and to examine how these may be modified by signals likely to occur during vascular injury or as a result of implantation of vascular prostheses. Endothelial cells of the pulmonary circulation are now known, both from in vivo and in vitro studies, to be highly active and capable of selectively metabolizing blood-borne substrates including peptides, biogenic amines, prostaglandins, and adenine nucleotides, and of degrading a variety of drugs and anesthetics to spare the systemic c i rc~la t ion .~ In addition, pulmonary endothelial cells possess receptors for a spectrum of agonists and hemostatic factors. The receptor-mediated responses of endothelial cells include release of substances that affect vascular tone and blood fluidity. Thus, the presence or absence of endothelium determines (via endotheliumdependent substances) whether the outcome of interaction with, for example, platelet products, results in vasospastic or vasodilatory responses of the vascular In addition endothelial cells engage in complex interactions with neutrophils and complement components that have important bearing on inflammatory processes.s The activities of pulmonary endothelium are not limited to constitutive properties that depend on an intact monolayer. Endothelial cells are also capable of inducible functions, thus they can respond to stimuli in ways that alter their hemostatic and immunologic potential and that alter their shape and behavior.6 Many of these responses can be viewed as activation phenomena and involve increased migration, division, and phagocyt~sis.~ Endothelial activation responses seem to involve changes in intracellular calcium levels and alterations in adenylate cyclase and protein kina~e.'.~

The Production of Platelet-Activating Factor by Cultured Human Endothelial Cells: Regulation and Function

Abstract: Under usual physiological conditions, the vascular endothelium must present a nonthrombogenic surface to the blood to prevent diffuse thrombosis (reviewed by Gingrich and Hoak, 1979). The mechanism(s) for this characteristic of endothelial cells has not been elucidated and is the subject of intense investigation. However, there are other circumstances in which the rapid, specific attraction of blood cells to the endothelium is essential to maintain vascular integrity and to respond to extra-vascular events. In the first instance, damage to the endothelium must be repaired to prevent hemorrhage and exudation. Clinical observations and studies of organ perfusion in vitro (Gimbrone et al., 1969; Kitchens and Weiss, 1975) have provided compelling evidence that platelets are critical in maintaining vascular integrity under basal conditions. These observations suggest that platelets interact with the endothelial cells continuously in vivo. With respect to the second situation, circulating leukocytes bind to the end othelium (margination) in response to appropriate soluble stimuli (reviewed by Harlan, 1985) and emigrate from the vasculature to sites of inflammation such as infection. The latter response must involve a specific targeting mechanism, which presumably would include the endothelium, to attract leukocytes to the appropriate sites. Accordingly, the recently described production of procoagulant activities [e.g., coagulation factors (Rodgers and Shuman, 1983) and glycoproteins similar to platelet adhesive molecules (Fitzgerald et al., 1985)] and chemotactic factors [e.g., platelet-derived growth factor (DiCorleto and Bowen-Pope, 1983)] by endothelium may be viewed as homeostatic responses.

Perspectives in inflammation, neoplasia, and vascular cell biology

Abstract: This book contains 25 selections. Some of the titles are: Characterization of cDNAs for the Human Interleukin-2 Receptor; Regulation of the Epidermal Growth Factor Receptor by Phosphorylation; Endothelial Cell Proteases and Cellular Invasion; Structure and Chromosomal Localization of the Human Lymphotoxin Gene; and Vascular Endothelial Cells in Cell-Mediated Immunity: Adoptive Transfer with In Vitro Conditioned Cells is Genetically Restricted at the Endothelial Cell Barrier.

The Extracellular Matrix as a Modulator of Angiogenesis

Abstract: Endothelium is comprised of heterogeneous cell populations residing in a variety of vascular beds. The endothelial cells resident in these diverse vascular beds or regions exhibit a broad range of diversity in their functions and appearances in addition to their shared common features such as non-thrombogenicity, polarity, and transport functions. Response to injury (neovascularization) is a response common to all endothelial cell populations, yet the responses vary depending on whether the endothelial cells are derived from large vessels or the microvasculature. Another factor thought to play an important role in the modulation of endothelial cell behavior in response to injury is the extracellular matrix. Large-vessel endothelial cells respond to injury by sheet migration/proliferation until the defect is covered. Evidence has been accrued supporting the concept that the underlying matrix determines, in part, the migration and proliferation rates, possibly via modulating cytoskeletal organization of the cells. In addition, the continual synthesis and secretion of matrix components by the responding cells appear to be crucial in the response to injury. Although microvascular endothelial cells respond to injury by migration and proliferation as do the large vessel endothelial cells, they migrate through interstitial tissue and ultimately form capillaries. Recent evidence has demonstrated that matrix composition can affect proliferation rate, matrix synthesis, and multicellular organization during the neovascularization process. In addition, matrix organization appears to influence differentiation of microvascular endothelial cells, specifically the ability of selected endothelial cell populations to form fenestrations. Thus, matrix composition and organization appear to play significant roles in orchestrating the growth and differentiation of endothelial cells during the highly integrated series of responses known as neovascularization.

Immunochemical comparison of peptide angiogenic factors.

Abstract: A panel of 40 monoclonal antibodies was constructed in response to cationic endothelial cell growth factor (c-ECGF), the cationic peptide mitogen isolated from endothelial mitogen. The monoclonal antibodies were assayed by dot blot for immunoreactivity to various other peptide angiogenic factors. The panel of monoclonal antibodies to c-ECGF exhibited complete cross-reactivity with pituitary fibroblast growth factor and sarcoma-derived growth factor. A group of 28 monoclonal antibodies was found to exhibit reactivity to anionic endothelial mitogen (a-ECGF), brain fibroblast growth factor, endothelial cell growth factor, and retina-derived growth factor. None of the monoclonal antibodies was found to react with epidermal growth factor or platelet-derived growth factor. These data provide an immunological basis for grouping heparin-binding endothelial cell growth factors into anionic and cationic groups.

An endothelial cell growth factor derived from human lung carcinoma cells grown in serum-free medium.

Abstract: A factor that stimulates the proliferation of human umbilical vein endothelial cells has been shown to be present in serum-free medium conditioned by the prior growth of a cell line (1PT) derived from a poorly differentiated bronchial carcinoma. Preliminary characterization of this factor has revealed that it is a heat-labile, acid-stable proteinaceous material, the activity of which is not diminished by treatment with a reducing agent. In its partially purified state it has been shown to be anionic and to be associated with material exhibiting a broad molecular weight range of 35 X 10(3) to 100 X 10(3). It does not bind strongly to heparin-Sepharose and its mitogenic effect on endothelial cells is not potentiated by heparin. These properties suggest that this factor may differ from other previously described tumour-derived endothelial mitogens.

Endothelial Cell Growth Factor and Its Receptor

Abstract: A new family of anionic polypeptide mitogens has been defined on the basis of biochemical and biological homologies (1,2,3,4). This polypeptide family structurally encompases endothelial cell growth factor (3), acidic-fibroblast growth factor (4), class I-heparin-binding growth factor and the hypothalamus- (5), brain- (6), eye- (7) and retina-derived (8) growth factors. These endothelial cell growth factor (ECGF) polypeptides stimulate endothelial cell DNA synthesis (9) and migration (10) in vitro and induce angiogenesis in vivo (). The proliferative and chemotactic activities of ECGF are potentiated by the glycosaminoglycan, heparin (11,12). This property is a unique attribute of the ECGF polypeptide family (1,2,11,12) and may involve the induction of a stable structural protein conformation by a non-covalent association between the glycosaminoglycan and the polypeptide (11).