Fibroblast growth factor 2 control of vascular tone

Zhou, Ming; Sutliff, Roy L.; Rutgeerts, Paul; Lorenz, John N.; Hoying, James B.; Haudenschild, Christian C.; Yin, Moying; Coffin, J. Douglas; Kong, Ling; Kranias, Evangelia G.; Luo, Wusheng; Boivin, Gregory P.; Duffy, John; Pawlowski, Sharon A.; Doetschman, Thomas

doi:10.1038/nm0298-201

Cited by 344 publications

(289 citation statements)

References 44 publications

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“…47 In addition, FGF-2 has been shown to play an important role in controlling vascular tone, which is essential in blood pressure regulation. 48 The role of new vessel growth in this model of acute ischemia is not clear, and is likely to be less important than the aforementioned mechanisms.…”

Section: Figure 7 Histology At Day 7 After Implantation Showing the Imentioning

confidence: 94%

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

et al. 2001

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Stimulating angiogenesis by gene transfer approaches offers the hope of treating tissue ischemia which is untreatable by currently practiced techniques of vessel grafting and bypass surgery. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) are potent angiogenic molecules, making them ideal candidates for novel gene transfer protocols designed to promote new blood vessel growth. In this study, an ex vivo gene therapy approach utilizing cell encapsulation was employed to deliver VEGF and FGF-2 in a continuous and localized manner. C(2)C(12) myoblasts were genetically engineered to secrete VEGF(121), VEGF(165) and FGF-2. These cell lines were encapsulated in hollow microporous polymer membranes for transplantation in vivo. Therapeutic efficacy was evaluated in a model of acute skin flap ischemia. Capsules were positioned under the distal, ischemic region of the flap. Control flaps showed 50% necrosis at 1 week. Capsules releasing either form of VEGF had no effect on flap survival, but induced a modest increase in distal vascular supply. Delivery of FGF-2 significantly improved flap survival, reducing necrosis to 34.2% (P < 0.001). Flap vascularization was significantly increased by FGF-2 (P < 0.01), with numerous vessels, many of which had a large lumen diameter, growing in the proximity of the implanted capsules. These results demonstrate that FGF-2, delivered from encapsulated cells, is more efficacious than either VEGF(121) or VEGF(165) in treating acute skin ischemia and improving skin flap survival. Furthermore, these data attest to the applicability of cell encapsulation for the delivery of angiogenic factors for the treatment and prevention of tissue ischemia

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Section: Figure 7 Histology At Day 7 After Implantation Showing the Imentioning

confidence: 94%

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

et al. 2001

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“…The generation of Fgf2-knockout mice has been described elsewhere (10). A fragment of the Fgf2 gene was replaced with a 3.2-kb hypoxanthine guanine phosphoribosyltransferase (Hprt) minigene, effectively removing the first 59 amino acids, which are important for heparin and receptor binding and for mitogenic activity.…”

Section: Methodsmentioning

confidence: 99%

“…Because of these findings, we investigated whether FGF-2 was chondroprotective in vivo. Fgf2 -/-mice are viable, fertile, and morphologically indistinguishable from their wildtype (WT) littermates under normal conditions (10). We examined the knee articular cartilage of naive Fgf2 -/-and Fgf2 ϩ/ϩ mice, and then we compared both agerelated cartilage degeneration in Fgf2 -/-and Fgf2 ϩ/ϩ mice and cartilage degeneration following surgical destabilization of the medial meniscus (DMM), a wellestablished model of OA.…”

mentioning

confidence: 99%

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

Chia¹,

Sawaji²,

Burleigh³

et al. 2009

Arthritis & Rheumatism

184

172

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Objective. We have previously identified in articular cartilage an abundant pool of the heparin-binding growth factor, fibroblast growth factor 2 (FGF-2), which is bound to the pericellular matrix heparan sulfate proteoglycan, perlecan. This pool of FGF-2 activates chondrocytes upon tissue loading and is released following mechanical injury. In vitro, FGF-2 suppresses interleukin-1-driven aggrecanase activity in human cartilage explants, suggesting a chondroprotective role in vivo. We undertook this study to investigate the in vivo role of FGF-2 in murine cartilage.Methods. Basal characteristics of the articular cartilage of Fgf2 -/-and Fgf2 ؉/؉ mice were determined by histomorphometry, nanoindentation, and quantitative reverse transcriptase-polymerase chain reaction. The articular cartilage was graded histologically in aged mice as well as in mice in which osteoarthritis (OA) had been induced by surgical destabilization of the medial meniscus. RNA was extracted from the joints of Fgf2 -/-and Fgf2 ؉/؉ mice following surgery and quantitatively assessed for key regulatory molecules. The effect of subcutaneous administration of recombinant FGF-2 on OA progression was assessed in Fgf2 -/-mice.Results. Fgf2 -/-mice were morphologically indistinguishable from wild-type (WT) animals up to age 12 weeks; the cartilage thickness and proteoglycan staining were equivalent, as was the mechanical integrity of the matrix. However, Fgf2 -/-mice exhibited accelerated spontaneous and surgically induced OA. Surgically induced OA in Fgf2 -/-mice was suppressed to levels in WT mice by subcutaneous administration of recombinant FGF-2. Increased disease in Fgf2 -/-mice was associated with increased expression of messenger RNA of Adamts5, the key murine aggrecanase. Conclusion. These data identify FGF-2 as a novel endogenous chondroprotective agent in articular cartilage.The structural integrity of articular cartilage is determined principally by homeostasis of the 2 major macromolecules of the extracellular matrix, type II collagen and the chondroitin sulfate-rich proteoglycan aggrecan. In healthy tissue, there is a balance between anabolic (synthetic) and catabolic (degradative) processes that allows matrix turnover. Excessive catabolic activity results in matrix breakdown, a hallmark of osteoarthritis (OA). One key early event in matrix breakdown is loss of aggrecan, which is caused by aggrecanase enzymes, members of the ADAMTS family. In humans, ADAMTS-4 and ADAMTS-5 are thought to be the major aggrecanases in cartilage (1,2). In the mouse, deletion of ADAMTS-5, but not ADAMTS-4, was shown to protect against the development of OA and inflammatory arthritis, suggesting that ADAMTS-5 is the main murine aggrecanase (3,4).We have identified fibroblast growth factor 2 (FGF-2) as a potential regulatory molecule in articular cartilage. It is bound to the heparan sulfate chains of the proteoglycan perlecan in the pericellular matrix of hu-

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“…Individual FGFs play important roles in various physiological and pathological processes, including embryonic development, cell growth, tissue repair, morphogenesis, in¯ammation, angiogenesis, vascular tone (Zhou et al, 1998), and tumor growth and invasion (reviewed by Mason, 1994). FGF-1 (acidic FGF) and FGF-2 (basic FGF) were identi®ed as mitogens for a variety of cell types (Gospodarowicz et al, 1978(Gospodarowicz et al, , 1986, whereas FGF-3 (int-2), FGF-4 (hst/K-FGF) and FGF-5 were ®rst identi®ed as oncogenes (reviewed by Basilico and Moscatelli, 1992;Burgess and Maciag, 1989).…”

Section: Introductionmentioning

confidence: 99%

Human fibroblast growth factor-18 stimulates fibroblast cell proliferation and is mapped to chromosome 14p11

Wang

Qiu

1999

Oncogene

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Fibroblast growth factor 2 control of vascular tone

Cited by 344 publications

References 44 publications

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

Delivery of FGF-2 but not VEGF by encapsulated genetically engineered myoblasts improves survival and vascularization in a model of acute skin flap ischemia

Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS‐5 and delays cartilage degradation in murine osteoarthritis

Human fibroblast growth factor-18 stimulates fibroblast cell proliferation and is mapped to chromosome 14p11

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