The role of fibroblast growth factors in vascular development (original) (raw)
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Regulation of vascular development by fibroblast growth factors
Cell and Tissue Research, 2003
Fibroblast growth factors (FGFs) are potent stimulators of angiogenesis in vitro and in vivo. However, the precise role of FGFs and vascular development in normal and pathological tissue has long remained ill defined. Recently, substantial progress has been made toward a better understanding of their role. Genetic studies in mice or in culture systems indicate a role for FGFs in vessel assembly and sprouting. FGFs also stimulate blood vessel branching and lymphangiogenesis. The molecular mechanisms by which FGFs mediate angiogenesis are also better understood. Finally, the FGF/ FGF-receptor system has become a focus for the development of novel therapeutic strategies for the treatment of angiogenesis-related diseases such as tissue ischemia.
Angiogenic growth factors in neural embryogenesis and neoplasia
The American journal of pathology, 1995
Blood vessels have the power to increase within themselves which is according to the necessity whether natural or diseased As afurther proof that this is a general principle, we find that aU growing parts are much more vascular than those that are come to theirfull growth; because growth is an operation beyond the simple support ofthepart. This is the reason whyyoung animals are more vascular than those that arefuUgrown. This is not peculiar to the natural operation of growth, but applies also to disease and restoration." John Hunter, 1728-1793) Angiogenesis, the growth of new blood vessels from those preexisting in tissue, is crucial to both human1 and in vivo experimental brain tumor growth.2'3 It is also an integral process of central nervous system embryogenesis.4 The angiogenic cascade begins with enzymatic degradation of the basement membrane, which permits migration and proliferation of endothelial cells and finally culminates in capillary morphogenesis.56 Angiogenic factors (AFs) stimulate in vivo neovascularization and are called "direct" when they stimulate endothelial cell division or migration in vivo and in vitro. "Indirect" AFs have no direct mitogenic effect on endothelial cells in vitro but are able to promote angiogenesis in vivo, probably in part by stimulation of target cells to release direct AFs.7 8 Determining events leading to angiogenesis include release of AFs, secretion of proteases that release AFs stored in the extracellular matrix, chemotaxis for macrophages which subsequently release AFs, and the release of endothelial cells from inhibitory control. Once stimulated, endothelial cells ostensibly are programmed to release protease, migrate, divide, form a lumen, and secrete a basal lamina.56 This review will 1) discuss some of the structural, biochemical, and biological characteristics of AFs, 2) summarize the evidence for their implication in neural embryogenesis and neoplasia, and 3) emphasize that identical AFs are involved in both of these processes. These AFs include fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factors (TGFs) a and (3, and platelet-derived growth factor (PDGF). Angiogenic Growth Factors FGF The FGF family9 is composed of at least nine related mitogens that affect a variety of cells of neuroectodermal or mesenchymal origin. FGF-1, or acidic FGF, and FGF-2 or basic FGF, share 53% sequence homology. While both are potent angiogenic factors,7 basic FGF is more effective than acidic FGF. The FGF family consists of structurally related proteins ranging from 16 to 35 kd. They all have a strong affinity for heparin and are often associated with the heparan sulfate proteoglycans (HSPGs) present in the basement membrane and extracellular matrix. The two classes of FGF receptors consist of high-affinity membrane tyrosine kinase receptors and low-affinity cell surface receptors which are HSPGs. The high-affinity
Fibroblast growth factor signaling in the vasculature
Current atherosclerosis reports, 2015
Despite their discovery as angiogenic factors and mitogens for endothelial cells more than 30 years ago, much remains to be determined about the role of fibroblast growth factors (FGFs) and their receptors in vascular development, homeostasis, and disease. In vitro studies show that members of the FGF family stimulate growth, migration, and sprouting of endothelial cells, and growth, migration, and phenotypic plasticity of vascular smooth muscle cells. Recent studies have revealed important roles for FGFs and their receptors in the regulation of endothelial cell sprouting and vascular homeostasis in vivo. Furthermore, recent work has revealed roles for FGFs in atherosclerosis, vascular calcification, and vascular dysfunction. The large number of FGFs and their receptors expressed in endothelial and vascular smooth muscle cells complicates these studies. In this review, we summarize recent studies in which new and unanticipated roles for FGFs and their receptors in the vasculature ha...
Chemistry & Biology, 2014
Angiogenesis contributes to the development of numerous disorders. Even though fibroblast growth factors (FGFs) were discovered as mediators of angiogenesis more than 30 years ago, their role in developmental angiogenesis still remains elusive. We use a recently described chemical probe, SSR128129E (SSR), that selectively inhibits the action of multiple FGF receptors (FGFRs), in combination with the zebrafish model to examine the role of FGF signaling in vascular development. We observe that while FGFR signaling is less important for vessel guidance, it affects vascular outgrowth and is especially required for the maintenance of blood vessel integrity by ensuring proper cell-cell junctions between endothelial cells. In conclusion, our work illustrates the power of a small molecule probe to reveal insights into blood vessel formation and stabilization and thus of broad interest to the vascular biology community.
FGF-dependent metabolic control of vascular development
Nature, 2017
Blood and lymphatic vasculatures are intimately involved in tissue oxygenation and fluid homeostasis maintenance. Assembly of these vascular networks involves sprouting, migration and proliferation of endothelial cells. Recent studies have suggested that changes in cellular metabolism are important to these processes. Although much is known about vascular endothelial growth factor (VEGF)-dependent regulation of vascular development and metabolism, little is understood about the role of fibroblast growth factors (FGFs) in this context. Here we identify FGF receptor (FGFR) signalling as a critical regulator of vascular development. This is achieved by FGF-dependent control of c-MYC (MYC) expression that, in turn, regulates expression of the glycolytic enzyme hexokinase 2 (HK2). A decrease in HK2 levels in the absence of FGF signalling inputs results in decreased glycolysis, leading to impaired endothelial cell proliferation and migration. Pan-endothelial- and lymphatic-specific Hk2 kn...
The biology of vascular endothelial growth factors
Cardiovascular Research, 2005
The discovery of the vascular endothelial growth factor (VEGF) family members VEGF, VEGF-B, placental growth factor (PlGF), VEGF-C and VEGF-D and their receptors VEGFR-1,-2 and-3 has provided tools for studying the vascular system in development as well as in diseases ranging from ischemic heart disease to cancer. VEGF has been established as the prime angiogenic molecule during development, adult physiology and pathology. PlGF may primarily mediate arteriogenesis, the formation of collateral arteries from preexisting arterioles, with potential future therapeutic use in for example occlusive atherosclerotic disease. VEGF-C and VEGF-D are primarily lymphangiogenic factors, but they can also induce angiogenesis in some conditions. While many studies have addressed the role of angiogenesis and the blood vasculature in human physiology, the lymphatic vascular system has until recently attracted very little attention. In this review, we will discuss recent advances in angiogenesis research and provide an overview of the molecular players involved in lymphangiogenesis.
Fibroblast Growth Factor-2 Selectively Stimulates Angiogenesis of Small Vessels in Arterial Tree
Arteriosclerosis, Thrombosis, and Vascular Biology, 2000
There is a critical need for quantifiable models of angiogenesis in vivo, and in general, differential effects of angiogenic regulators on vascular morphology have not been measured. Because the potent angiogenic stimulators fibroblast growth factor (FGF)-2 (basic FGF) and vascular endothelial growth factor (VEGF) are reported to stimulate angiogenesis through distinct signaling pathways, we hypothesized that FGF-2 stimulates vascular morphology differently than does VEGF and that stimulation of angiogenesis by FGF-2 is directly correlated to FGF receptor density. FGF-2 was applied at embryonic day 7 (E7), E8, or E9 to the quail chorioallantoic membrane (CAM); subsequent response of the arterial tree was measured by the fractal dimension (D f ), a mathematical descriptor of complex spatial patterns, and by several generational branching parameters that included vessel length density (L v ). After application of FGF-2 at E7, arterial density increased according to D f as a direct function of increasing FGF-2 concentration, and FGF-2 stimulated the growth of small vessels, but not of large vessels, according to L v and other branching parameters. For untreated control specimens at E7, L v of small vessels and D f were 11.1Ϯ1.6 cm Ϫ1 and 1.38Ϯ0.01, respectively; at E8, after treatment with 5 g FGF-2/CAM for 24 hours, L v of small vessels and D f increased respectively to 22.8Ϯ0.7 cm Ϫ1 and 1.49Ϯ0.02 compared with 16.3Ϯ0.9 cm Ϫ1 and 1.43Ϯ0.02 for PBS-treated control specimens. Application of FGF-2 at E8 and E9 did not significantly increase arterial density. By immunohistochemistry, the expression of 4 high-affinity tyrosine kinase FGF receptors was significantly expressed at E7, when CAM vasculature responded strongly to FGF-2 stimulation, but FGF receptor expression decreased throughout the CAM by E8, when vascular response to FGF-2 was negligible. In conclusion, the "fingerprint" vascular pattern elicited by FGF-2 was distinct from vascular patterns induced by other angiogenic regulators that included VEGF 165 , transforming growth factor-1, and angiostatin. (Arterioscler Thromb Vasc
Biochemical and Biophysical Research Communications, 1992
Vascular endothelial growth factor (VEGF), also known as vascular permeability factor or vasculotropin, is a recently characterized endothelial-specific mitogen which is angiogenic in vivo. Here we demonstrate that VEGF is angio !! enic in vitro: when added to microvascular endothelial cells grown on the surface o threedimensional collagen form capillary-like els, VEGF induces the cells to invade the underlying matrix and to tu fi ules, with an optimal effect at When compared to basic fibroblast growth factor ap roximately 2.2nM (lOOng/ml). (FGF) :: at equimolar (OSnM) concentrations, VEGF was about half as potent. The most striking effect was seen in combination with bFGF: when added simultaneously, VEGF and bFGF induced an in vitro angiogenic response which was far greater than additive, and which occurred with greater rapidity than the response to either cytokine alone. These results demonstrate that like bFGF, VEGF induces an angiogenic response via a direct effect on endothelial cells, and that by acting in concert, these two cytokines have a potent synergistic effect on the induction of angiogenesis in vitro. We suggest that the synergism between VEGF and bFGF plays an important role in the control of angiogenesis in vivo. o 1992 Academic press, I,,~.
The Regulation of Blood Vessel Growth by Vascular Endothelial Growth Factor
Annals of the New York Academy of Sciences, 1995
A fundamental property of vascular endothelial cells is the ability to proliferate and form a network of capillaries.'.2 This process is known as "angiogenesis" and requires at least three steps: i) degradation of the extracellular matrix of a local venule, ii) chemotaxis of endothelial cells toward an angiogenic stimulus, and iii) proliferation of endothelial cells. Angiogenesis is prominent during embryonic development and somatic growth but in a normal adult it only takes place following injury or, in a cyclical fashion, in the endometrium and in the ovary.'%2 Angiogenesis plays a significant role in the pathogenesis of a variety of disorders including cancer, proliferative retinopathies, rheumatoid arthritis or psoriasis. Therefore, inhibition of angiogenesis may constitute an attractive strategy for the treatment of such disorders. Conversely, disorders characterized by inadequate tissue perfusion such as obstructive atherosclerosis and diabetes are expected to benefit from agents able to promote endothelial cell growth and angiogenesis. A variety of factors have been identified as potential positive regulators of angiogenesis: aFGF, bFGF, EGF, TGF-a, TGF-P, PGE2, monobutyrin, TNF-a, PD-ECGF, angiogenin and interleukin-8.'~~ This article will review a recently identified family of directly-acting endothelial cell mitogens and angiogenic factors known as vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF).3,4 These factors are products of the same gene and, by alternative exon splicing, may exist in four different iso-form^.^-^ Recent studies point to VEGF as a major regulator of physiological and pathological angiogenesis. Furthermore, the angiogenic activity of VEGF appears to be sufficient to achieve therapeutic benefit in animal models of coronary or limb ischemia. Biological Properties of VEGF A unique aspect of VEGF is its target all specificity.' VEGF is a potent mitogen (ED5o 2-10 pM) for vascular endothelial cells, but it is apparently devoid of mitogenic activity for other cell types.'-" VEGF is also able to induce a marked angiogenic response in the chick chorioallantoic membrane.'O-I2 VEGF also proa Corresponding author.