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• W2145174900 abstract "Editorial FocusEndothelial FGF receptor signaling: angiogenic versus atherogenic effectsJ. Koudy WilliamsJ. Koudy WilliamsWake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salem, North CarolinaPublished Online:01 Jan 2011https://doi.org/10.1152/ajpheart.01037.2010This is the final version - click for previous versionMoreSectionsPDF (69 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat members of the fibroblast growth factor (FGF) family have been shown experimentally to stimulate angiogenesis through their mitotic and migratory effects on endothelial cells and by promoting endothelial integrity (2, 8). As such, they have been explored as a potential treatment of ischemic disease in several clinical trials (6). In their article in the issue of the American Journal of Physiology-Heart and Circulatory Physiology, Che et al. (2) report that an overexpression of FGF receptor (FGFR) accelerates the development of atherosclerosis in a transgenic mouse model, casting doubt on using this treatment in patients with preexisting atheromatous disease.In the study by Che et al. (2), FGFR2-overexpressing mice were crossed with atherosclerosis-prone apolipoprotein E (ApoE)-deficient mice. The mice were fed a Western diet, and the vascular end points were compared with those of ApoE-deficient mice (as the control group). After 8 wk of consuming the diet, the FGFR2 mice had double the amount of atherosclerosis compared with the ApoE-deficient mice. This was associated with an increased arterial expression of adhesion molecules and smooth muscle cell proliferation, with associated concurrent increased PDGF-B and early growth response (Egr)-1 expression. Additionally, an overexpression of FGFR2 was associated with increased serum and in vitro measures of oxidation and inflammation. Interestingly, the knockdown of p21cip1 (a cell cycle-dependent kinase inhibitor) reversed these effects of FGFR2 expression, implicating FGFR2 in atherogenesis through a p21cip1 mechanism. The authors then concluded that the clinical use of FGFR2 therapy in promoting angiogenesis for ischemic diseases may be suspect in the presence of atherosclerosis.That FGFR2 may affect atherogenesis has been previously reported. Probably the most direct correlation between FGFR2 and atherogenesis was reported by Raj et al. (9). In this study, ApoE-knockout mice were fed an FGF-2 tyrosine kinase inhibitor SU-5402. These mice had less atherosclerosis than control ApoE-knockout mice receiving no inhibitor. Unlike the study of Che et al. (2), the study by Raj et al. (9) included evidence that FGFR2 affects plaque inflammation and oxidation processes. This was illustrated by a reduced number of macrophages, a reduced expression of monocyte chemoattractant protein-1, and a reduced expression of cyclooxygenase and CD36 in the SU-5402-treated mice.If FGFR2 modulates plaque inflammation (not just serum measures of inflammation and oxidation), it may have important implications for plaque stability/instability and risk of plaque rupture. FGFR2 has also been implicated in further (but associated) inflammatory pathways. Chan et al. (1) reported that FGF-2 modulates pathways associated with NF-κB production (9), such as VCAM and ICAM. An interesting pathway by which FGFR2 may affect atherogenesis and plaque stability is through its effects on heparin sulfate and perlecan-induced cell proliferation and inflammation (3–5). It has also been reported that VEGF indirectly simulates smooth muscle cell proliferation and migration through the stimulation of FGF-2 and TGF-β1 (7), thus involving further inflammatory processes.A potential interesting aspect of the FGFR2 effects on both atherogenesis and angiogenesis is its effects on the proliferation of vasa vasorum in the atherosclerotic artery wall. Proliferation of vasa into the intima-media of atherosclerotic arteries is viewed as both a good thing (provides nutrition to a thickened artery) and a bad thing [may predispose to intra-arterial hemorrhage and plaque rupture (11)]. Important to the FGFR2 story, plaque size and cell proliferation are not the sole stimulant of neovascularization within the atheroma (11). In relation to the studies reporting the marked effects of FGFR2 on inflammatory processes (1, 3–5, 7, 9), it is probably more important that FGFR2 affects oxidation processes and possibly oxidative stress in the lesions, which are probably the most potent stimulus for angiogenesis (11).Therefore, the significance of the study by Che et al. (2) is not so much that FGFR2 is associated with atherosclerosis, which has been previously reported (9), but that it more precisely identifies the signaling processes by which FGFR2 affects atherogenesis. This then elegantly constructs a working model of how FGFR2 may affect atherogenesis. Even more importantly, the studies confirm the role of FGFR2 in regulating the inflammatory processes that may change a stable atherosclerotic lesion to a more unstable lesion capable of rupture. This information, in the face of FGFR2 being used to promote angiogenesis clinically, warrants the caution of using this approach to promote angiogenesis in the presence of atherosclerotic disease.While great strides in medicine are made by developing a specific target for therapy, this study is a good lesson in how affecting one single molecule can be beneficial for one disease process (treatment of ischemic disease) but harmful to another (atherosclerotic disease). As with all therapeutic approaches, one needs to weigh the cost-to-benefit ratio to each individual patient.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).REFERENCES1. Chan J, Prado-Lourenco L, Khachigian LM, Bennett MR, Di Bartolo BA, Kavurma MM. TRAIL promotes VSMC proliferation and neointima formation in a FGF-2, Sp1 phosphorylation-, and NFkappaB-dependent manner. Circ Res 106: 1061–1071, 2010.Crossref | PubMed | ISI | Google Scholar2. Che J, Okigaki M, Takahashi T, Katsume A, Adachi Y, Yamaguchi S, Matsunaga S, Takeda M, Matsui A, Kishita E, Ikeda K, Yamada H, Matsubara H. Endothelial FGF receptor signaling accelerates atherosclerosis. Am J Physiol Heart Circ Physiol (October 15, 2010). https://doi.org/10.1152/ajpheart.00075.2010.PubMed | ISI | Google Scholar3. Francis DJ, Parish CR, McGarry M, Santiago FS, Lowe HC, Brown KJ, Bingley JA, Hayward IP, Cowden WB, Campbell JH, Campbell GR, Chesterman CN, Khachigian LM. Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation. Circ Res 92: e70–e77, 2003.Crossref | PubMed | ISI | Google Scholar4. Kennett EC, Rees MD, Malle E, Hammer A, Whitelock JM, Davies MJ. Peroxynitrite modifies the structure and function of the extracellular matrix proteoglycan perlecan by reaction with both the protein core and the heparin sulfate chains. Free Radic Biol Med 49: 282–293, 2010.Crossref | PubMed | ISI | Google Scholar5. Kinsella MG, Irvin C, Reidy MA, Wight TN. Removal of herparan sulfate by heparinase treatment inhibits FGF-2-dependent smooth muscle cell proliferation in injured rat carotid arteries. Atherosclerosis 175: 51–57, 2004.Crossref | PubMed | ISI | Google Scholar6. Lekas M, Lekas P, Latter DA, Kutryk MB, Stewart DJ. Growth factor-induced therapeutic neovascularization for ischaemic vascular disease: time for a re-evaluation? Curr Opin Cardiol 21: 376–384, 2006.Crossref | PubMed | ISI | Google Scholar7. Li D, Zhang C, Song F, Lubenec I, Tian Y, Song QH. VEGF regulates FGF-2 and TGF-beta1 expression in injury endothelial cells and mediates smooth muscle proliferation and migration. Microvasc Res 77: 134–142, 2008.Crossref | PubMed | ISI | Google Scholar8. Murakami M, Nguyen LT, Zhuang ZW, Moodie KL, Carmeliet P, Stan RV, Simons M. The FGF system has a key role in regulating vascular integrity. J Clin Invest 118: 3355–3366, 2008.Crossref | PubMed | ISI | Google Scholar9. Raj T, Kanellakis P, Pomilio G, Jennings G, Bobik A, Agrotis A. Inhibition of fibroblast growth factor receptor signaling attenuates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 26: 1845–1851, 2006.Crossref | PubMed | ISI | Google Scholar10. Tsuboi R, Sato Y, Rifkin DB. Correlation of cell migration, cell invasion, receptor number, proteinase production, and basic fibroblast growth factor levels in endothelial cells. J Cell Biol 10: 511–517, 1990.Crossref | ISI | Google Scholar11. Williams JK, Armstrong ML, Heistad DD. Vasa vasorum in atherosclerotic coronary arteries: responses to vasoactive stimuli and regression of atherosclerosis. Circ Res 62: 515–523, 1988.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. Koudy Williams, Wake Forest Inst. for Regenerative Medicine, Wake Forest Univ. Health Sciences, 391 Technology Way, Winston-Salem, NC, 27101 (e-mail: [email protected]edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Collections Cited ByRole of lipids and intraplaque hypoxia in the formation of neovascularization in atherosclerosis22 August 2017 | Annals of Medicine, Vol. 49, No. 8Janus-like role of fibroblast growth factor 2 in arteriosclerotic coronary artery disease: Atherogenesis and angiogenesisAtherosclerosis, Vol. 229, No. 1 More from this issue > Volume 300Issue 1January 2011Pages H27-H28 Copyright & PermissionsCopyright © 2011 the American Physiological Societyhttps://doi.org/10.1152/ajpheart.01037.2010PubMed21057042History Published online 1 January 2011 Published in print 1 January 2011 Metrics" @default.
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