Showing papers on "Angiogenesis published in 1989"

Vascular endothelial growth factor is a secreted angiogenic mitogen

Abstract: Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.

Vascular permeability factor, an endothelial cell mitogen related to PDGF

Abstract: Vascular permeability factor (VPF) is a 40-kilodalton disulfide-linked dimeric glycoprotein that is active in increasing blood vessel permeability, endothelial cell growth, and angiogenesis. These properties suggest that the expression of VPF by tumor cells could contribute to the increased neovascularization and vessel permeability that are associated with tumor vasculature. The cDNA sequence of VPF from human U937 cells was shown to code for a 189-amino acid polypeptide that is similar in structure to the B chain of platelet-derived growth factor (PDGF-B) and other PDGF-B-related proteins. The overall identity with PDGF-B is 18%. However, all eight of the cysteines in PDGF-B were found to be conserved in human VPF, an indication that the folding of the two proteins is probably similar. Clusters of basic amino acids in the COOH-terminal halves of human VPF and PDGF-B are also prevalent. Thus, VPF appears to be related to the PDGF/v-sis family of proteins.

Induction of angiogenesis during the transition from hyperplasia to neoplasia

Abstract: It is now well established that unrestricted growth of tumours is dependent upon angiogenesis. Previous studies on tumour growth, however, have not revealed when or how the transition to an angiogenic state occurs during early tumour development. The advent of transgenic mice carrying oncogenes that reproducibly elicit tumours of specific cell types is providing a new format for studying multi-step tumorigenesis. In one of these models, transgenic mice expressing an oncogene in the beta-cells of the pancreatic islets heritably recapitulate a progression from normality to hyperplasia to neoplasia. We report here that angiogenic activity first appears in a subset of hyperplastic islets before the onset of tumour formation. A novel in vitro assay confirms that hyperplasia per se does not obligate angiogenesis. Rather, a few hyperplastic islets become angiogenic in vitro at a time when such islets are neovascularized in vivo and at a frequency that correlates closely with subsequent tumour incidence. These findings suggest that induction of angiogenesis is an important step in carcinogenesis.

Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis.

Abstract: Vascular permeability factor (VPF) is an Mr 40-kD protein that has been purified from the conditioned medium of guinea pig line 10 tumor cells grown in vitro, and increases fluid permeability from blood vessels when injected intradermally. Addition of VPF to cultures of vascular endothelial cells in vitro unexpectedly stimulated cellular proliferation. VPF promoted the growth of new blood vessels when administered into healing rabbit bone grafts or rat corneas. The identity of the growth factor activity with VPF was established in four ways: (a) the molecular weight of the activity in preparative SDS-PAGE was the same as VPF (Mr approximately 40 kD); (b) multiple isoforms (pI greater than or equal to 8) for both VPF and the growth-promoting activity were observed; (c) a single, unique NH2-terminal amino acid sequence was obtained; (d) both growth factor and permeability-enhancing activities were immunoadsorbed using antipeptide IgG that recognized the amino terminus of VPF. Furthermore, 125I-VPF was shown to bind specifically and with high affinity to endothelial cells in vitro and could be chemically cross-linked to a high-molecular weight cell surface receptor, thus demonstrating a mechanism whereby VPF can interact directly with endothelial cells. Unlike other endothelial cell growth factors, VPF did not stimulate [3H]thymidine incorporation or promote growth of other cell types including mouse 3T3 fibroblasts or bovine smooth muscle cells. VPF, therefore, appears to be unique in its ability to specifically promote increased vascular permeability, endothelial cell growth, and angio-genesis.

Mechanochemical switching between growth and differentiation during fibroblast growth factor-stimulated angiogenesis in vitro: role of extracellular matrix.

Abstract: The angiogenic factor, basic fibroblast growth factor (FGF), either stimulates endothelial cell growth or promotes capillary differentiation depending upon the microenvironment in which it acts. Analysis of various in vitro models of spontaneous angiogenesis, in combination with time-lapse cinematography, demonstrated that capillary tube formation was greatly facilitated by promoting multicellular retraction and cell elevation above the surface of the rigid culture dish or by culturing endothelial cells on malleable extracellular matrix (ECM) substrata. These observations suggested to us that mechanical (i.e., tension-dependent) interactions between endothelial cells and ECM may serve to regulate capillary development. To test this hypothesis, FGF-stimulated endothelial cells were grown in chemically defined medium on bacteriological (nonadhesive) dishes that were precoated with different densities of fibronectin. Extensive cell spreading and growth were promoted by fibronectin coating densities that were highly adhesive (greater than 500 ng/cm2), whereas cell rounding, detachment, and loss of viability were observed on dishes coated with low fibronectin concentrations (less than 100 ng/cm2). Intermediate fibronectin coating densities (100-500 ng/cm2) promoted cell extension, but they could not completely resist cell tractional forces. Partial retraction of multicellular aggregates resulted in cell shortening, cessation of growth, and formation of branching tubular networks within 24-48 h. Multicellular retraction and subsequent tube formation also could be elicited on highly adhesive dishes by overcoming the mechanical resistance of the substratum using higher cell plating numbers. Dishes coated with varying concentrations of type IV collagen or gelatin produced similar results. These results suggest that ECM components may act locally to regulate the growth and pattern-regulating actions of soluble FGF based upon their ability to resist cell-generated mechanical loads. Thus, we propose that FGF-stimulated endothelial cells may be "switched" between growth, differentiation, and involution modes during angiogenesis by altering the adhesivity or mechanical integrity of their ECM.

Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor.

Abstract: Cloning and sequencing of the complementary DNA for platelet-derived endothelial cell growth factor indicates that it is a novel factor distinct from previously characterized proteins. The factor, a protein with a relative molecular mass of about 45,000, stimulates endothelial cell growth and chemotaxis in vitro and angiogenesis in vivo.

Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells.

Abstract: A growth factor with specificity for vascular endothelial cells has been identified in conditioned medium of pituitary-derived folliculo stellate cells. This factor, named folliculo stellate-derived growth factor (FSdGF), was purified to homogeneity by a combination of heparin-Sepharose affinity chromatography, Bio-Gel P-60 exclusion chromatography, Mono S ion-exchange chromatography, and hydrophobic chromatography on a C4 reverse-phase HPLC column. FSdGF was characterized as a homodimer composed of two subunits with a molecular mass of 23 kDa. FSdGF was a potent mitogen for vascular endothelial cells with activity detectable at 25 pg/ml and saturation at 500 pg/ml. It did not stimulate the proliferation of other cell types such as bovine vascular smooth muscle cells, corneal endothelial cells, adrenal cortex cells, granulosa cells, BALB/MK cells, or BHK-21 cells. Microsequencing revealed an N-terminal sequence having no significant homology to any known protein. The release of FSdGF by pituitary cells and its target cell specificity raise the possibility that FSdGF may play a role in angiogenesis.

Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells.

Abstract: An endothelial cell growth factor with unique specificity for vascular endothelial cells has been purified from the conditioned medium of the AtT-20 pituitary cell line. This growth factor, which has been characterized as a homodimer composed of two subunits with mol. wts of 23 kd is a potent mitogen for vascular endothelial cells in vitro with activity detectable at 50 pg/ml and saturation at 1 ng/ml. It was also angiogenic in vivo. In contrast with other endothelial mitogens of the fibroblast growth factor family, it has a unique target cell specificity. It did not stimulate the growth of other cell types of the vascular system such as vascular smooth muscle cells or that of mesoderm and neuroectoderm derived cells. Microsequencing revealed an amino-terminal sequence with no homology to any known protein. The release of this novel endothelial cell growth factor by pituitary derived cells and its unique target cell specificity suggest that it could play an important role in the angiogenic process.

In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases.

Abstract: The role of basic fibroblast growth factor-(bFGF) induced proteinases in basement membrane (BM) invasion by bovine capillary endothelial (BCE) cells was studied using a quantitative in vitro assay previously described (Mignatti et al., 1986). 125I-iododeoxyuridine-labeled BCE cells were grown for 72 h on the human amnion BM, and cell invasion was determined by measuring the radioactivity associated with the tissue after removal of the noninvasive cell layer. BCE cells were noninvasive under normal conditions. Addition of human bFGF to either the BM or to the stromal aspect of the amnion induced BCE cell invasion with a dose-dependent response. This effect was maximal in the presence of 70 ng/ml bFGF, and was inhibited by anti-FGF antibody. Transforming growth factor beta, as well as plasmin inhibitors and anti-tissue type plasminogen activator antibody inhibited BCE cell invasion. The tissue inhibitor of metalloproteinases, 1-10 phenanthroline, anti-type IV and anti-interstitial collagenase antibodies had the same effect. On the contrary, anti-stromelysin antibody and Eglin, an inhibitor of elastase, were ineffective. The results obtained show that both the plasminogen activator-plasmin system and specific collagenases are involved in the invasive process occurring during angiogenesis.

Relationship between vasculogenesis, angiogenesis and haemopoiesis during avian ontogeny.

Abstract: Quail-chick intracoelomic grafts of organ rudiments were used to study the origin of endothelia and haemopoietic cells during avian organogenesis in conjunction with the monoclonal antibody QH1 which recognizes the quail haemangioblastic lineage. Results differed according to the germ-layer constitution of the grafted rudiments. In the case of the limb buds, endothelial cells from the host invaded the graft through an angiogenic process. Haemopoietic progenitors from the host also colonized the grafted bone marrow. In contrast, rudiments of internal organs provided their own contingent of endothelial precursors, a process termed vasculogenesis. Nevertheless, haemopoietic cells in these organs were all derived from the host. In the lung, this extrinsic cell population appeared regularly scattered around the parabronchi and had a macrophage-like phenotype. In the pancreas, the granulocytes which differentiate as dense aggregates located in the wall of the largest vessels were extrinsic. Similarly in the spleen, a mesodermal primordium that develops in close association with the pancreatic endoderm, endothelial cells were intrinsic and haemopoietic cells host-derived. This study demonstrates that, in ontogeny, vascularization obeys different rules depending on which germ layer the mesoderm is associated with: in mesodermal/ectodermal rudiments angiogenesis is the rule; in mesodermal/endodermal rudiments, vasculogenesis occurs. However, in these internal organs undergoing vasculogenesis, endothelial and haemopoietic cells have separate origins. We put forward the hypothesis that the endoderm induces the emergence of endothelial cells in the associated mesoderm. Formation of blood stem cells may also involve interactions between endoderm and mesoderm, but in this case the responding capacity of the mesoderm appears restricted to the paraaortic region.

Embryonic Origins and Assembly of Blood Vessels

Abstract: Embryonic blood vessels develop in two ways: angiogenesis, which is growth by budding, branching, and elongation of existing vessels, and in situ formation of endothelial vesicles that coalesce with elongating vessels. It is assumed that the former is more prevalent, with the latter restricted to vessels that form near the endoderm:mesoderm interface. Neither the relative contributions of each of these processes in the formation of specific blood vessels nor the origins of precursors (angioblasts) of these intraembryonic endothelial populations are known. Antibodies that recognize quail endothelial cells can be used to follow the movements and differentiation of endothelial cell precursors after the transplantation of putative precursor populations from quail into chick embryos. Using this method, it has been shown that all intraembryonic mesodermal tissues, except the prechordal plate, contain angiogenic precursors. After transplantation some angioblasts move in all directions away from the site of implantation, invading surrounding mesenchyme and contributing to the formation of arteries, veins, and capillaries in a wide area. Although it is clear that these invasive angioblasts, which behave unlike any other embryonic mesenchymal cell type, are found throughout the embryo, it is not known whether they represent a unique endothelial cell type in mature blood vessels. Irrespective of their original location in the donor embryo, transplanted angioblasts will form vascular channels that are appropriate for the tissues surrounding their site of implantation. These results indicate that the control over vascular assembly resides within the connective-tissue-forming mesenchyme of the embryo.

Control of angiogenesis with synthetic heparin substitutes

Abstract: Many diseases are dominated by persistent growth of capillary blood vessels. Tumor growth is also angiogenesis-dependent. Safe and effective angiogenesis inhibitors are needed to determine whether control of angiogenesis would be therapeutic. Heparin and certain steroids, administered together, can inhibit angiogenesis in a synergistic manner. This "pair" effect suggested that specific hydrophilic cycloamyloses may be suitable heparin substitutes. beta-Cyclodextrin tetradecasulfate administered with a steroid inhibits angiogenesis at 100 to 1000 times the effectiveness of heparin in the chick embryo bioassay. This cyclic oligosaccharide also augments the anti-angiogenic effect of angiostatic steroids against corneal neovascularization in rabbits when beta-cyclodextrin tetradecasulfate and a steroid are inserted into the cornea or applied topically as eyedrops.

Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts.

Abstract: Better understanding of the micromilieu of human tumors in situ is mandatory for further improvement of diagnostic and therapeutic interventions. Since investigations of untreated tumors of a wide size range are precluded in humans for ethical reasons, size-dependent changes in the pathophysiology of primary and metastatic human tumors were studied using "tissue-isolated" xenografts in nude rats. Tumor types included lung and breast cancers, ovarian and thyroid carcinomas, uterus tumors, and melanomas. A 10-fold variation in weight-adjusted tumor perfusion indicated large variations in angiogenesis which were unrelated to tumor type. Flow values obtained were consistent with data from clinical observations and were comparable to that in isografted rodent tumors. Using actual consumption and supply rates, maximum oxygen and glucose uptake rates were calculated for each tumor type. The capacity to consume oxygen and glucose varied 9-fold and 4-fold, respectively. However, considering actual consumption rates, blood flow was the principal modulator of substrate supply and tumor metabolism in these human tumor xenografts. Consequently, therapeutically relevant parameters of the metabolic micromilieu largely depended on the efficacy of the tumor circulation. Hereby, high metabolic rates concomitant with high flow values coincided with rapid tumor growth. Thus, in order to design the best individualized therapy, flow-related data should supplement histological classification and clinical staging and grading. Further development of relatively noninvasive technologies (magnetic resonance imaging, magnetic resonance spectroscopy, or positron emission tomography) might permit such monitoring.

Tumor-related angiogenesis

Abstract: In recent years, tumor-related angiogenesis has become an important field of research in oncology. It could be stated that growth of solid tumors is completely dependent on neovascularization to provide the tumor with all required nutrients. Special compounds (tumor angiogenesis factor[s]) are released by tumor cells into the environment to stimulate different types of normal cells to become active for the tumor. In particular, endothelial cells of neighboring capillaries are induced to react. They disintegrate their own basal lamina, detach from their neighbors, enter the extracellular matrix, and migrate toward the tumor mass. Cell divisions occur within such sprouts, thereby increasing the number of migrating endothelial cells. Strands of such cells are formed, and inter- and intracellular lumina develop. Loops of these hollow strands anastomose to form a network of new vessels which become connected with the blood circulation. The tumor mass thus becomes vascularized and can continue to grow. The prevention of neoangiogenesis has an enormous impact on cancer treatment by inhibiting the growth of the tumor. In this review, all important aspects of tumor-related angiogenesis are presented.

The response of the microvascular system to radiation: a review.

Abstract: The microvasculature is a ubiquitous organ system having a major role in the pathogenesis of radiation damage to normal tissues. Although the kinetics of radiation damage to endothelial cells is similar to other tissues (as reflected by Do and Dq) the late effect is a manifestation of injury, not only to the endothelial cell population, but also to the basement membrane. Tissue damage is progressive. The initial expression of radiation injury is an increased permeability leading to changes in the extracellular milieu. There is an irregular proliferation of endothelial cells leading to capillaries of irregular diameter and shape. Fibrous proliferation increases the histohematic barrier and is ultimately reflected in a loss of parenchymal cells. Replacement fibrosis progresses until a steady state is reached where the surviving parenchymal cells can be sustained by the microvasculature. The clinical significance depends on the role of the organ system involved. For patients who have medical conditions which adversely effect the stability of the vascular system (hypertension, diabetes, etc.), the expressions of radiation injury may be more severe and increase the morbidity associated with these diseases. Angiogenesis in granulation tissue is less radiosensitive than in steady-state parenchymal tissues. Wound healing is not significantly affected bymore » commonly used therapeutic doses of irradiation, 40-50 Gy delivered 4-6 weeks preoperatively or postoperatively early in the development of the granulation tissue, but may be complicated where a significant degree of fibrosis has developed. The vascular responses leading to telangiectasia were discussed. 39 references.« less

Fetal Vasculogenesis and Angiogenesis in Human Placental Villi

Abstract: Placental villi of 5 exactly defined early human specimens ranging from day 21 post conception (pc) until day 42 pc and from an additional 43 specimens from about 5 to 40 weeks menstrual age have been analyzed ultrastructurally with regard to fetal vasculogenesis and angiogenesis The following results were obtained: The first cells differentiating at day 21 pc probably originating from mesenchymal precursors, are macrophage-like cells At almost the same time, mesenchymal cells transform into haemangioblastic cell cords which are the forerunners of the capillary endothelium and haematopoietic stem cells A third cell population related to the fetal circulatory system and derived from the mesenchymal cells are presumptive pericytes Capillary formation takes place by the aggregation of haemangioblastic cells which are attached to each other by intercellular junctions The lumen is formed by the dehiscence of the intercellular clefts A capillary basal lamina cannot be detected earlier than in the last trimester In this last period of gestation fetal villous angiogenesis takes place by the proliferation of the existing endothelium and pericytes rather than via haemangioblastic cells

Special Report The Complexity of Endothelial Cells: A Review

Abstract: This review of the biology peculiar to endothelial cells (ECs) is based mainly on data available within the last decade. The functions described refer to angiogenesis, coagulation, and EC-platelet interaction, inflammation and immune response, synthesis of stromal components, vascular tone regulation, and miscellaneous metabolic activities. Emphasis is placed on the marked variability of ECs from tissue to tissue and from one species to another. This heterogeneity is evident morphologically, functionally, and in the response of ECs to injury.

Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans.

Abstract: Transplantation of isolated islets of Langerhans is frequently followed by early loss of islet function. Because whether this is caused by insufficient vascularization or graft rejection is unknown, angiogenesis and microvascularization of islet grafts were studied in vivo by means of intravital microscopy. After transplantation of syngeneic islets in hamster dorsal skin-fold chambers, 97% (n = 66) of the islets exhibited the first signs of angiogenesis at days 2-4, characterized by sinusoidal sacculations and capillary sprouts. After 10 days, angiogenesis was completed, consisting of a microvascular network similar to those of islets in situ: arterial supply, afferent and efferent capillary loops, and venular drainage. Functional density of microvessels was 700.1 +/- 127.0 cm-1, and erythrocyte velocity was 0.58 +/- 0.35 mm/s. Intracellular insulin was demonstrated immunohistochemically. Electron-microscopic studies revealed normal fine structure of the capillary wall. The model allows in vivo analysis of microvascular phenomena occurring in host-vs.-graft reaction after allogeneic and xenogeneic islet transplantation. Furthermore, it may be used to quantitatively assess immunosuppressive regimens.

Hyaluronan and angiogenesis.

Abstract: Remodelling tissues, in both normal and pathological situations, show a greatly increased synthesis and turnover of hyaluronan. An essential part of these processes is new blood vessel formation. Whereas native hyaluronan has been reported to inhibit angiogenesis in vivo, partial degradation products (4-25 disaccharide units) have been found to stimulate angiogenesis in several in vivo systems. Examination of the effect of hyaluronan and its oligosaccharides on cultured cells suggests that these effects are due to the direct action of hyaluronan on endothelial cells. Native HA inhibits endothelial cell proliferation and disrupts cell-cell/cell-substrate interactions at physiological concentration. Angiogenic oligosaccharides induce both endothelial proliferation and migration, possibly via a receptor-mediated mechanism. Thus the metabolic state of hyaluronan could have profound effects on tissue neovascularization.

Basic fibroblast growth factor in the chick embryo: immunolocalization to striated muscle cells and their precursors.

Abstract: The identification of acidic and basic fibroblast growth factors (FGFs) in a number of embryonic tissue extracts has implicated these growth factors in the regulation of a variety of embryonic events including angiogenesis, eye development, and muscle differentiation. Lack of information concerning the cellular distribution of the growth factor within these tissues has made it extremely difficult to assign developmental roles to FGF. We have localized bFGF in the developing chick embryo using immunohistochemical techniques and our monospecific polyclonal rabbit anti-human bFGF IgG. The spatial pattern for bFGF localization was highly specific. The anti-human bFGF antibodies recognized striated muscle cells and their precursors in 2-6-d chick embryos. Myocardium, somite myotome, and limb bud muscle all stain positively for bFGF. In addition, the anti-human bFGF antibodies localized specifically to the cell, rather than to the extracellular matrix or nucleus of myotubes. The localization of bFGF demonstrated here provides further support for the hypothesis (Clegg et al., 1987; Seed et al., 1988) that this growth factor is involved in muscle development.

Monoclonal antibodies against heparin-binding growth factor II/basic fibroblast growth factor that block its biological activity: invalidity of the antibodies for tumor angiogenesis

Abstract: Two monoclonal antibodies (mAbs) against bovine heparin-binding growth factor II (HBGF-II)/basic fibroblast growth factor (bFGF) were obtained from mouse hybridoma cell lines. They were highly specific for bFGF from bovine, human, and mouse sources and did not cross-react with bovine heparin-binding growth factor I (HBGF-I)/acidic fibroblast growth factor (aFGF). The immunoglobulin class and subclass of these mAbs were IgG1, K. The apparent dissociation constant (Kd) for bFGF of these mAbs ranged from 10(-9) to 10(-10) M. One mAb (bFM-2) also cross-reacted with heat-inactivated bFGF, while the other mAb (bFM-1) did not, suggesting that bFM-1 recognized the conformation of the bFGF molecule necessary for its biological activity. These mAbs inhibited growth of cultured bovine capillary endothelial cells in both the presence and absence of exogenous bFGF, indicating the autocrine action of this growth factor in in vitro growth of these cells. On the other hand, injection of these hybridoma cell lines s.c. into the backs of athymic mice resulted in development of highly vascularized solid tumors and a sustained high level of anti-bFGF activity in the blood of the tumor-bearing mice. These findings suggest that bFGF is not essential as an autocrine or paracrine growth factor for angiogenesis in vivo. These mAbs should be useful in further studies on the physiological role and the conformation-function relationship of bFGF because they block its biological activity.

Interactions between cancer cells and the microvasculature: a rate-regulator for metastasis.

Abstract: Hematogenous metastasis is a major consideration in the staging, treatment and prognosis of patients with cancer. Key events affecting hematogeneous metastasis occur in the microvasculature. This is a brief, selective review of some interactions involving cancer cells and the microvasculature in pathologic sequence, specifically: (1) intravasation of cancer cells; (2) the arrest of circulating cancer cells in the microvasculature; (3) cancer cell trauma associated with arrest; (4) microvascular trauma; (5) the inflammatory; and (6) the hemostatic coagulative responses associated with arrest, and finally (7) angiogenesis, leading to tumor vascularization. The evidence shows that through a series of complex interactions with cancer cells, the microvasculature acts as a rate-regulator for the metastatic process, in addition to providing routes for cancer cell dissemination and arrest sites for cancer cell emboli.

Regulation of endothelial cell growth, architecture, and matrix synthesis by TGF-beta.

Abstract: Transforming growth factor-beta (TGF-beta) has profound effects on all cell types making up the vasculature, including endothelial cells, smooth muscle cells, and adventitial connective tissue. As such, it plays a prominent role not only in the physiologic vasculogenesis and angiogenesis characteristic of embryogenesis and inflammation and repair but also in vascular disorders such as the arterial thickening associated with pulmonary hypertension. The actions of TGF-beta on these vascular cells in vitro and in vivo are extremely complex. In vitro, TGF-beta inhibits both the proliferation and migration of endothelial cells in monolayer culture, but it promotes organization of the cells into tubelike structures in three-dimensional culture in collagen gels. TGF-beta also increases synthesis of fibronectin and decreases secretion of proteases by both endothelial cells and fibroblasts; the resultant changes in matrix composition could mediate the effects of TGF-beta on both the growth and phenotype of these cells, and overexpression could contribute to fibrosis. TGF-beta also regulates the synthesis by endothelial cells of platelet-derived growth factor, which can stimulate growth of vascular smooth muscle cells. In vivo, TGF-beta stimulates neovascularization at local sites of injection and also is angiogenic when assayed in the rabbit cornea or on the chick chorioallantoic membrane. However, because angiogenesis involves the participation of many different cell types, effects of TGF-beta on inflammatory cells must also be considered. Thus, the ability of TGF-beta to chemoattractant macrophages and to increase expression by the cells of mRNAs for several growth factors known to act on endothelial cells, smooth muscle cells, and fibroblasts must also be considered.

Growth Factors For Wound Healing

Abstract: The process of wound healing begins immediately following surface lesions or when skin proteins become exposed to radiation, chemical damage or extreme temperatures. Wound repair requires close control of degradative and regenerative processes, involving numerous cell types and complex interactions between multiple biochemical cascades. Growth factors released in the traumatized area promote cell migration into the wound area (chemotaxis), stimulate the growth of epithelial cells and fibroblasts (mitogenesis), initiate the formulation of new blood vessels (angiogenesis), and stimulate matrix formation and remodeling of the affected region. Animal studies have shown that exogenously added growth factors can accelerate the normal healing process. Growth factors have also been used successfully in humans to treat previously incurable wounds. The most intensively studied growth factors are EGF, FGFs, PDGF, TGF-α, and TGF-βs. Each of these factors is currently the focus of intense commercial development.