Showing papers on "Vascular endothelial growth factor A published in 1992"

Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.

Abstract: Inefficient vascular supply and the resultant reduction in tissue oxygen tension often lead to neovascularization in order to satisfy the needs of the tissue. Examples include the compensatory development of collateral blood vessels in ischaemic tissues that are otherwise quiescent for angiogenesis and angiogenesis associated with the healing of hypoxic wounds. But the presumptive hypoxia-induced angiogenic factors that mediate this feedback response have not been identified. Here we show that vascular endothelial growth factor (VEGF; also known as vascular permeability factor) probably functions as a hypoxia-inducible angiogenic factor. VEGF messenger RNA levels are dramatically increased within a few hours of exposing different cell cultures to hypoxia and return to background when normal oxygen supply is resumed. In situ analysis of tumour specimens undergoing neovascularization show that the production of VEGF is specifically induced in a subset of glioblastoma cells distinguished by their immediate proximity to necrotic foci (presumably hypoxic regions) and the clustering of capillaries alongside VEGF-producing cells.

Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.

Abstract: Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular proliferations. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.

The fms-Like Tyrosine Kinase, a Receptor for Vascular Endothelial Growth Factor

Abstract: The fms-like tyrosine kinase (Flt) is a transmembrane receptor in the tyrosine kinase family. Expression of flt complementary DNA in COS cells conferred specific, high-affinity binding of vascular endothelial growth factor, also known as vascular permeability factor (VEGF-VPF), a factor that induces vascular permeability when injected in the guinea pig skin and stimulates endothelial cell proliferation. Expression of Flt in Xenopus laevis oocytes caused the oocytes to release calcium in response to VEGF-VPF. These findings show that flt encodes a receptor for VEGF-VPF.

Molecular and Biological Properties of the Vascular Endothelial Growth Factor Family of Proteins

Abstract: I. Introduction THE establishment of a vascular supply is a critical requirement for cellular inflow of nutrients, outflow of waste products, and gas exchange in most tissues and organs (1). In endocrine glands, the vascularization not only serves such needs but also provides a pathway for the specific secretory products (2, 3). Furthermore, in the anterior pituitary (4–6) and in the adrenal medulla (7, 8), an unusual angioarchitecture, where a portal capillary plexus delivers venous blood originating from an adjacent gland, is intimately involved in the control of the secretory activity. In the adrenal medulla, this vascular design may even determine the ultimate secretory product (8). Not surprisingly, the cardiovascular system is the first organ system to develop and reach a functional state in an embryo (9–12). In the human, primitive blood vessels appear as early as day 15, and a circulation with a beating heart is already established by the end of the third week.

Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth

Abstract: Hepatocyte Growth Factor (HGF, also known as Scatter Factor) is a powerful mitogen or motility factor in different cells, acting through the tyrosine kinase receptor encoded by the MET protooncogene Endothelial cells express the MET gene and expose at the cell surface the mature protein (p190MET) made of a 50 kD (alpha) subunit disulfide linked to a 145-kD (beta) subunit HGF binding to endothelial cells identifies two sites with different affinities The higher affinity binding site (Kd = 035 nM) corresponds to the p190MET receptor Sub-nanomolar concentrations of HGF, but not of a recombinant inactive precursor, stimulate the receptor kinase activity, cell proliferation and motility HGF induces repairs of a wound in endothelial cell monolayer HGF stimulates the scatter of endothelial cells grown on three-dimensional collagen gels, inducing an elongated phenotype In the rabbit cornea, highly purified HGF promotes neovascularization at sub-nanomolar concentrations HGF lacks activities related to hemostasis-thrombosis, inflammation and endothelial cells accessory functions These data show that HGF is an in vivo potent angiogenic factor and in vitro induces endothelial cells to proliferate and migrate

Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation

Abstract: Vascular endothelial growth factor (VEGF) is a secreted angiogenic mitogen whose target cell specificity appears to be restricted to vascular endothelial cells. Such factors are likely candidates for regulatory molecules involved in endothelial growth control. We have characterized the murine VEGF gene and have analysed its expression pattern in embryogenesis, particularly during brain angiogenesis. Analysis of cDNA clones predicted the existence of three molecular forms of VEGF which differ in size due to heterogeneity at the carboxy terminus of the protein. The predicted mature proteins consist of 120, 164 or 188 amino acid residues. Homodimers of the two lower molecular weight forms, but not of the higher molecular weight form, were secreted by COS cells transfected with the corresponding cDNAs and were equally potent in stimulating the growth of endothelial cells. During brain development, VEGF transcript levels were abundant in the ventricular neuroectoderm of embryonic and postnatal brain when endothelial cells proliferate rapidly but were reduced in the adult when endothelial cell proliferation has ceased. The temporal and spatial expression of VEGF is consistent with the hypothesis that VEGF is synthesized and released by the ventricular neuroectoderm and may induce the ingrowth of capillaries from the perineural vascular plexus. In addition to the transient expression during brain development, a persistent expression of VEGF was observed in epithelial cells adjacent to fenestrated endothelium, e.g. in choroid plexus and in kidney glomeruli. The data are consistent with a role of VEGF as a multifunctional regulator of endothelial cell growth and differentiation.

Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors

Abstract: Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), increases microvascular permeability and is a specific mitogen for endothelial cells. Expression of VPF/VEGF previously was demonstrated in a variety of tumor cells, in cultures of pituitary-derived cells, and in corpus luteum. Here we present evidence, by Northern analysis and in situ hybridization, that the VPF/VEGF gene is expressed in many adult organs, including lung, kidney, adrenal gland, heart, liver, and stomach mucosa, as well as in elicited peritoneal macrophages. The highest levels of VPF/VEGF transcripts were found in epithelial cells of lung alveoli, renal glomeruli and adrenal cortex, and in cardiac myocytes. The prominence of VPF/VEGF mRNA in these tissues suggests a possible role for VPF/VEGF in regulating baseline microvascular permeability, which is essential for tissue nutrition and waste removal. We also demonstrate particularly high VPF/VEGF mRNA levels in several human tumors, where it may be involved in promoting tumor angiogenesis and stroma generation, both as an endothelial cell mitogen and indirectly by its permeability enhancing effect that leads to the deposition of a provisional fibrin gel matrix.

Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing.

Abstract: Persistent microvascular hyperpermeability to plasma proteins even after the cessation of injury is a characteristic but poorly understood feature of normal wound healing. It results in extravasation of fibrinogen that clots to form fibrin, which serves as a provisional matrix and promotes angiogenesis and scar formation. We present evidence indicating that vascular permeability factor (VPF; also known as vascular endothelial growth factor) may be responsible for the hyperpermeable state, as well as the angiogenesis, that are characteristic of healing wounds. Hyperpermeable blood vessels were identified in healing split-thickness guinea pig and rat punch biopsy skin wounds by their capacity to extravasate circulating macromolecular tracers (colloidal carbon, fluoresceinated dextran). Vascular permeability was maximal at 2-3 d, but persisted as late as 7 d after wounding. Leaky vessels were found initially at the wound edges and later in the subepidermal granulation tissue as keratinocytes migrated to cover the denuded wound surface. Angiogenesis was also prominent within this 7-d interval. In situ hybridization revealed that greatly increased amounts of VPF mRNA were expressed by keratinocytes, initially those at the wound edge, and, at later intervals, keratinocytes that migrated to cover the wound surface; occasional mononuclear cells also expressed VPF mRNA. Secreted VPF was detected by immunofluoroassay of medium from cultured human keratinocytes. These data identify keratinocytes as an important source of VPF gene transcript and protein, correlate VPF expression with persistent vascular hyperpermeability and angiogenesis, and suggest that VPF is an important cytokine in wound healing.

Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells.

Abstract: Vascular endothelial growth factor (VEGF) is a 45kDa secreted peptide that has potent mitogenic activity specific for endothelial cells in vitro and the ability to induce a strong angiogenic response in vivo. In the present study, 24 h treatment with VEGF resulted in a stimulation of expression of the metalloproteinase, interstitial collagenase, at the protein and mRNA levels 2.5-3.0-fold in human umbilical vein endothelial cells but not in human dermal fibroblasts. The dose response curve for collagenase induction was biphasic with the peak stimulatory response obtained by treatment of cells with 10-100 ng/ml (0.2-2 nM) VEGF. The dose response curve for collagenase induction overlapped with, but was not identical to, the response curve for proliferation, which showed VEGF mitogenic activity between < or = 0.1-50 ng/ml (< or = 0.002-1 nM). There was no induction seen in expression of other members of the matrix metalloproteinase family, including the 72kDa type IV collagenase, the 92kDa type V collagenase, or stromelysin. Expression of transcripts for the major metalloproteinase inhibitor, tissue inhibitor of metalloproteinases, was also unaltered by treatment with VEGF (1-200 ng/ml). These studies demonstrate that in addition to stimulating proliferation of endothelial cells, VEGF can also induce the expression of the only metalloproteinase that can initiate degradation of interstitial collagen types I-III under normal physiological conditions. Both responses are likely to contribute to the angiogenic potential of this peptide.

Binding sites for vascular endothelial growth factor are localized on endothelial cells in adult rat tissues.

Abstract: Vascular endothelial growth factor (VEGF) is a secreted heparin-binding mitogen; its growth-promoting activity is limited to vascular endothelial cells in vitro and VEGF also stimulates angiogenesis in vivo. To identify target cells for VEGF and investigate the potential physiological role of this factor, iodinated recombinant human VEGF (125I-rhVEGF) was used for in vitro ligand autoradiography on tissue sections from adult rats. 125I-rhVEGF exhibited saturable, displaceable binding to a single class of sites with high affinity and low capacity in all tissues and organs examined. Colocalization of 125I-rhVEGF binding with Factor VIII-like immunoreactivity demonstrated binding sites associated with vascular endothelial cells of both fenestrated and nonfenestrated microvessels and the endothelium of large vessels, while no displaceable binding was evident on nonendothelial cells. Specific binding was associated with quiescent as well as proliferating vessels. These findings support the hypothesis that VEGF plays a specific role in both the maintenance and in the induction of growth of vascular endothelial cells.

Vascular endothelial growth factor messenger ribonucleic acid expression in the primate ovary.

Abstract: We studied the distribution of messenger RNA (mRNA) that encodes for vascular endothelial growth factor (VEGF) within the primate ovary by in situ hybridization and Northern analysis to determine if the presence of mRNA for this angiogenic factor is associated with structures within the ovary in which angiogenesis is thought to play a role in development and/or function. In situ hybridization to sections of cynomolgus ovaries with a 35S-labeled antisense RNA probe revealed specific tissue localization within the follicle as well as the corpus luteum, but not stromal tissue. Intense expression of mRNA for VEGF during the late follicular phase was confined to the maturing follicle which, we presume, was destined for ovulation. Hybridization within the corpus luteum exhibited a punctate pattern suggesting that there may be specific cells within the corpus luteum that express mRNA for VEGF. The expression of mRNA for VEGF during the early and late luteal phase of the menstrual cycle was studied by Northern an...

Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation.

Abstract: An association between malignancy and abnormal hemostasis has been appreciated for more than a hundred years.1.2 A broad spectrum of clinically significant hemostatic abnormalities (eg., migratory thrombophlebitis, hemorrhage, disseminated intravascular coagulation) afflicts as many as 15% of cancer patients, and hemostatic complications are the second most common cause of mortality in cancer. Only recently, however, has it been recognized that, in addition to a proclivity to systemic coagulation, cancer patients activate the clotting system locally and extravasdarly, depositing fibrin gels in solid tumors that serve as a provisional stroma and that have a role in the induction of mature tumor stroma. The Irish pathologist, R.A.Q. O'Meara, was the first to propose in the late 1950s that fibrin was deposited in solid tumors; however, his work was inconclusive because the techniques then available fbr identifylng fibrin in tissues were primitive and relatively nonspecific. The first solid evidence that fibrinogen-related proteins (FRP) were localized in solid tumors came fiom studies which showed that systemically administered fibrinogen, and also antifibrinogen antibodies, were selectively concentrated in animal and human tumors.2 Thereafter, seved groups demonstrated FRP in rat and human neoplasms by immunofluorescence. For some time there was considerable reluctance to accept even these findings. Valid questions were raised as to the specificity of the antibodies used, the generality of the observations, and the possibility ofartifict, arising from accumulation of FRP either postmortem or as tissues were being removed surg~cally. More recent work has W l y laid these doubts to rest.2 Moreover, immunohistochemical, electron microscopic, and, in some instances, biochemical studies

Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C.

Abstract: Platelet-derived growth factor and phorbol ester cause an increase in vascular endothelial growth factor (VEGF) mRNA expression in control NIH 3T3 fibroblasts and NIH 3T3 fibroblasts overexpressing human protein kinase C (PKC) α. In the case of phorbol ester-induced VEGF expression, the VEGF mRNA levels were significantly higher in cells overexpressing human PKC α as compared to control cells. In cells stimulated with platelet-derived growth factor or phorbol ester, induction of expression was lost after down-regulation of PKC. This indicates that PKC is involved in the signal transduction leading to VEGF expression.

Atrial natriuretic polypeptide as a novel antigrowth factor of endothelial cells.

Abstract: The migration and proliferation of endothelial cells play a pivotal role in various vascular diseases. We have previously reported that atrial natriuretic polypeptide (ANP) exerts an antigrowth effect on vascular smooth muscle cells via the guanylate cyclase-coupled mechanism. Because the endothelial cells are known to possess a large number of guanylate cyclase-coupled ANP receptors, we examined the action of ANP on the growth of endothelial cells. ANP (10(-7) and 10(-6) M) significantly attenuated serum-stimulated DNA synthesis of cultured bovine aortic endothelial cells with concomitant reduction of the increase in cell number. A ring-deleted analogue of ANP exerted less prominent antiproliferative action, and 8-bromo cyclic GMP (cGMP) mimicked the action of ANP, suggesting the involvement of cGMP cascade in the endothelial growth. Moreover, the proliferative action of exogenously administered basic fibroblast growth factor on endothelial cells was significantly attenuated by the simultaneously administered 8-bromo cGMP. Taken together, the present results demonstrate a potential novel role of ANP in the regulation of endothelial cell growth, which is implicated in angiogenesis or reendothelialization.

Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury.

Abstract: We studied the effects of factors associated with vascular injury on the production of endothelin-1 (ET-1) in cultured porcine aortic endothelial cells. ET-1 mRNA expression and peptide production in endothelial cells were increased by thrombin, transforming growth factor β1 (TGFβ1), interleukin-1 (IL-1) and tumor necrotizing factor α (TNFα). The analysis of the enhancer/promoter region of the human ET-1 gene showed that the ET-1 gene transcription is regulated in a cell-specific manner and is activated by thrombin, TGFβ1 and IL-1. These results suggest that the production of ET-1 in endothelial cells is regulated by factors associated with platelet aggregation, macrophage infiltration and the formation of atherosclerotic lesions.

Vascular endothelial cell growth factor C subunit

Abstract: Vascular endothelial cell growth factor C subunit DNA is prepared by polymerase chain reaction techniques. The DNA encodes a protein that may exist as either a heterodimer or homodimer. The protein is a mammalian vascular endothelial cell mitogen and as such is useful for the promotion of vascular development and repair. This unique growth factor is also useful in the promotion of tissue repair.

Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade.

Abstract: Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both overexpression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.

Endothelial cell dysfunctions

Abstract: General: Endothelial Cell Response to Normal and Abnormal Stimuli (M. Simionescu). Endothelial Cell Regrowth (M.A. Reidy, V. Lindner). Endothelial Cell in Inflammation and Immunity: LeukocyteMediated Endothelial Injury (R.K. Winn et al.). Endothelial Cell Adhesive Interactions (E. Dejana et al.). Endothelial Cells in the Viral Infection: Response of Human Vascular Cells to Viral Infection (N.A. Kefalides). Endothelial Cells in Hypertension, Hyperlipidemia, and Atherosclerosis: Endothelial Dysfunction and Atherosclerosis (R. Ross). Endothelial Cells in Diabetes: Vascular Endothelium and Diabetes Mellitus (R.S. Bar). Endothelial Cells in Neoplasia and Metastasis: The Microvascular Phases of Metastasis (L. Weiss, F.W. Orr). Endothelial Cells in Other Disturbances Twentythree additional articles. Index

Growth factors and corneal endothelial cells: III. Stimulation of adult human corneal endothelial cell mitosis in vitro by defined mitogenic agents.

Abstract: Human corneal endothelial cells (HCEC) do not mitose extensively in vivo after damage to the endothelial layer. However, HCEC will divide in vitro if cultured under appropriate conditions. We measured the ability of various sera, plasma, growth factors, and nutritional substances to stimulate mitosis of HCEC during 5 days of organ culture after a central freeze injury to the endothelium. Supplementation of a chemically defined medium (CDM) with 20% fetal human serum (FHS) induced significantly higher numbers of mitotic figures or labeled nuclei of human or cat corneas compared with paired corneas cultured in CDM alone. Furthermore, addition of 20% FHS produced more labeled nuclei than did addition of 20% fetal bovine serum or 20% adult human serum. Dialyzed fetal human serum failed to stimulate mitosis, indicating that one or more components of fetal human serum with molecular weight less than 12,000 are essential for mitosis. Human plasma also failed to stimulate mitosis, but an extract of human platelets significantly stimulated high levels of nuclear labeling, suggesting that growth factors contained in platelet granules were responsible for serum-stimulated mitosis of HCEC. Addition of 100 nM epidermal growth factor (EGF) or 10 microM insulin to CDM supplemented with low levels of adult human serum (0.5%) stimulated significantly higher numbers of labeled nuclei compared with paired corneas cultured with 0.5% adult human serum. Supplementation of corneal storage media (K-Sol and CSM) with a mixture of chemically defined agents consisting of EGF, insulin, transferrin, selenium, linoleic acid, and albumin stimulated significantly higher numbers of labeled nuclei compared with paired corneas cultured in the unsupplemented corneal storage media.(ABSTRACT TRUNCATED AT 250 WORDS)