Transforming Growth Factor-β Signal Transduction in Angiogenesis and Vascular Disorders

Bertolino, Philippe; Deckers, Martine; Lebrin, Franck; Dijke, Peter ten

doi:10.1378/chest.128.6_suppl.585s

Cited by 238 publications

(167 citation statements)

References 27 publications

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“…Additionally, bFGF is a heparin-binding protein involved in intestinal inflammation and it promotes angiogenesis through endothelial cell proliferation, migration, and differentiation, as well as proliferation of mesenchymal cells (67,154). Lastly, TGF-␤ is a pleiotropic angiogenic peptide growth factor that regulates proliferation, migration, differentiation, and proliferation in endothelial cells and ECM synthesis through signaling with its receptors TGFR-2 and -3 and is released by T cells during mucosal inflammation (17,150). Our data show all of these growth factors to be upregulated during experimental colitis (31), and these mediators are all crucial in directing endothelial cells to create new vasculature.…”

Section: Angiogenic Mediators In Ibd and Experimental Colitismentioning

confidence: 64%

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Chidlow

Shukla²,

Grisham³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

144

114

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Chidlow JH Jr, Shukla D, Grisham MB, Kevil CG. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol 293: G5-G18, 2007. First published April 26, 2007; doi:10.1152/ajpgi.00107.2007.-Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed. inflammation; T cells; growth factors; adhesion molecules; antiangiogenesis ANGIOGENESIS PLAYS AN IMPORTANT role in many chronic inflammatory diseases including but not limited to diabetic retinopathy, atherosclerosis, rheumatoid arthritis, hypercholesterolemia, and psoriasis. It has been suggested that the angiogenic components of these diseases contribute to and exacerbate disease conditions (26, 31). Recent findings, both clinical and experimental, indicate that angiogenesis also plays a crucial role in the inflammatory bowel diseases (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC) (31,37,58,131,155). Development of new vasculature during chronic inflammation may play a negative "pathological" role by contributing to increased inflammatory responses due to dysfunctional new vessel architecture and increases in the recruitment of inflammatory cell types. Importantly, recent data have shown that angiogenic inhibition during chronic inflammatory diseases attenuates further inflammation and disease pathology (31, 37, 51). As such, expanding our knowledge of how pathological angiogenesis occurs during IBD will further our ability to treat patients with these diseases. IBD PathogenesisCD and UC are idiopathic inflammatory disorders of the intestine and/or colon in which patients suffer from rectal bleeding, severe...

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Section: Angiogenic Mediators In Ibd and Experimental Colitismentioning

confidence: 64%

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Chidlow

Shukla²,

Grisham³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

144

114

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“…In many cell types, ALK5-driven TGF-␤ signaling is involved in the regulation of proliferation, differentiation, migration, and survival. 47 However, it is still debated whether TGF-␤ signaling plays a pro-or an antiatherogenic role in the endothelium. In mouse models of accelerated atherosclerosis, there is evidence for an antiatherogenic role for TGF-␤, for its partial disruption has been shown to induce expression levels of the proatherogenic leukocyte adhesive molecules ICAM-1 and VCAM-1 48 and to result in a more inflammatory and less fibrotic lesion type.…”

Section: Discussionmentioning

confidence: 99%

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis

Volger

Fledderus

Kisters

et al. 2007

The American Journal of Pathology

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Knowledge about the in vivo role of endothelium in chronic human atherosclerosis has mostly been derived by insights from mouse models. Therefore, we set out to establish by microarray analyses the gene expression profiles of endothelium from human large arteries, as isolated by laser microbeam microdissection, having focal atherosclerosis of the early or the advanced stage. Within individual arteries, the endothelial transcriptomes of the lesional and unaffected sides were compared pairwise, thus limiting genetic and environmental confounders. Specific endothelial signature gene sets were identified with changed expression levels in either early (n ‫؍‬ 718) or advanced atherosclerosis (n ‫؍‬ 403), relative to their paired plaque-free controls. Gene set enrichment analysis identified distinct sets of chemokines and differential enrichments of nuclear factor-B-, p53-, and transforming growth factor-␤-related genes in advanced plaques.

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“…Binding TGF-b1 to the receptor complex triggers activation of type I receptor, also termed activin receptor-like kinase (ALK), which initiates downstream signaling involving Smad transcription factors, mitogen-activated protein kinases (MAPK), and PI3K-Akt signaling (reviewed by Derynck and Zhang (2003)). TGF-b signaling is mediated by ALK5 and, in some cells, by ALK1 (Bertolino et al, 2005). ALK5 phosphorylates Smad2 and Smad3, while ALK1 activates Smad1 and Smad5, triggering their translocation to the nucleus together with Smad4 (Massague, 1998).…”

Section: Introductionmentioning

confidence: 99%

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

2006

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Transforming growth factor beta 1 (TGF-b1) is a potent tumor suppressor but, paradoxically, TGF-b1 enhances tumor growth and metastasis in the late stages of cancer progression. This study investigated the role of TGF-b type I receptor, ALK5, and three mitogen-activated protein kinases (MAPKs) in metastasis by breast cancer cell line MDA-MB-231. We show that autocrine TGF-b signaling in MDA-MB-231 cells is required for tumor cell invasion and tumor angiogenesis. Expression of kinaseinactive ALK5 reduces tumor invasion and formation of new blood vessels within the tumor orthotopic xenografts in severe combined immunodeficiency (SCID) mice. In contrast, constitutively active ALK5-T204D enhances tumor invasion and angiogenesis by stimulating expression of matrix metalloproteinase MMP-9/gelatinase-B. Ablation of MMP-9 in ALK5-T204D cells by RNA interference (RNAi) reduces tumor invasion and tumor growth. Importantly, RNAi-MMP-9 reduces tumor neovasculature and increases tumor cell death. Induction of MMP-9 by TGF-b-ALK5 signaling requires MEK-ERK but not JNK, p38 MAPK or Smad4. Dominant-negative MEK blocks and constitutively active MEK1 enhances MMP-9 expression. However, all three MAPK cascades (ERK, JNK and p38 MAPK) are required for TGF-b-mediated cell migration. Collectively, our results show that TGF-b-ALK5-MAPK signaling in tumor cells promotes tumor angiogenesis and MMP-9 is an important component of this program.

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Transforming Growth Factor-β Signal Transduction in Angiogenesis and Vascular Disorders

Cited by 238 publications

References 27 publications

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Distinctive Expression of Chemokines and Transforming Growth Factor-β Signaling in Human Arterial Endothelium during Atherosclerosis

ALK5 promotes tumor angiogenesis by upregulating matrix metalloproteinase-9 in tumor cells

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