Proinflammatory functions of vascular endothelial growth factor in alloimmunity

Reinders, Marlies E.J.; Sho, Masayuki; Izawa, Atsushi; Wang, Ping; Mukhopadhyay, Debabrata; Koss, Kerith E.; Geehan, Christopher; Luster, Andrew D.; Sayegh, Mohamed H.; Briscoe, David M.

doi:10.1172/jci200317712

Cited by 58 publications

(79 citation statements)

References 47 publications

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“…VEGF has been shown to reduce apoptosis in a large number of cells and cell lines, many of which express VEGF-R1. These include cancer cells, e.g., breast, prostate, and multiple myeloma cells (1,22,27) as well as normal neurons (33), monocytes (36), skeletal myoblasts (18) in mammals, and hematopoietic cells in both mammals and Drosophila (6,16). The mechanisms through which VEGF reduces apoptosis, as shown here, and increases podocyte cell survival (14) are unknown.…”

Section: Discussionmentioning

confidence: 91%

Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes

Foster¹,

Saleem²,

Mathieson³

et al. 2005

American Journal of Physiology-Renal Physiology

111

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Vascular endothelial growth factor (VEGF) is anti-cytotoxic in podocytes. Moreover, it has been suggested that nephrin, a cell adhesion molecule of the podocyte slit diaphragm, can contribute to antiapoptotic mechanisms in these cells. We therefore investigated whether VEGF signals to reduce apoptosis and the role of nephrin in this survival mechanism. Flow cytometry showed that podocytes with nephrin mutations had a significantly greater proportion of apoptosis. Although VEGF reduced apoptosis in human conditionally immortalized podocytes [wild-type (WT)] by 18.1% of control ( P < 0.001), it was unable to do so in nephrin-deficient human conditionally immortalized podocytes. Moreover, Western blotting and immunodetection with an anti-nephrin antibody showed that the phosphorylation of nephrin, compared with serum-starved WTs, was significantly increased (ratio of 3.36 ± 1.2 to control, P < 0.05) by VEGF treatment and significantly reduced by treatment with a neutralizing VEGF monoclonal antibody (mAb) (ratio of 0.2 ± 0.09 to control, P < 0.05). The AKT signaling pathway has been implicated in nephrin-mediated inhibition of apoptosis in transfected cells, but the role of this pathway has not previously been shown in podocytes. Surprisingly, exogenous VEGF decreased AKT/PKB phosphorylation in normal podocytes but increased it in nephrin-deficient podocytes. We suggest therefore that both exogenous and endogenous (podocyte derived) VEGF can stimulate the phosphorylation of nephrin and through this action may prevent podocyte apoptosis. However, the involvement of AKT in this survival response in normal human podocytes is not clear.

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Section: Discussionmentioning

confidence: 91%

Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes

Foster¹,

Saleem²,

Mathieson³

et al. 2005

American Journal of Physiology-Renal Physiology

111

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“…A study by Detmar et al (42) reported that transgenic overexpression of VEGF 164 in the skin of mice led to large increases in leukocyte rolling and firm adhesion and that these mice showed increased vascular density composed of immature vessels, indicating a molecular link between leukocyte recruitment and angiogenesis. Recent reports also demonstrate that VEGF-A is a potent immune modulator under several conditions such as ischemiareperfusion and alloimmunity (126,156). VEGF-A stimulation of human umbilical vein endothelial cells increases the expression of adhesion molecules, such as ICAM-1, VCAM-1, and selectins (68,75).…”

Section: Angiogenic Mediators In Ibd and Experimental Colitismentioning

confidence: 99%

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

139

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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“…43 It is also interesting, in light of the success of anti-VEGF therapies in the management of neovascular AMD, that VEGF itself increases expression of endothelial cell adhesion molecules and elevates recruitment of macrophages and neutrophils under some conditions, in addition to its well-appreciated direct effects on vascular growth. 44,45 How might macrophages protect against macular degeneration?…”

Section: How Might Macrophages Promote Macular Degeneration?mentioning

confidence: 99%

Macrophages in neovascular age-related macular degeneration: friends or foes?

Skeie

Mullins

2008

Eye

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The events that lead to choroidal neovascularization in eyes with age-related macular degeneration are poorly understood. One possibility that has been explored in a number of studies is that macrophages can promote neovascular changes. In this paper, we summarize the evidence for inflammation in general and macrophages in particular in pathologic neovascularization, and discuss how the diverse functions of these cells may promote or inhibit macular disease. We also discuss some of the conflicting findings regarding the role of macrophages in experimental choroidal neovascularization in mouse models, and suggest areas for future research.

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Proinflammatory functions of vascular endothelial growth factor in alloimmunity

Cited by 58 publications

References 47 publications

Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes

Vascular endothelial growth factor and nephrin interact and reduce apoptosis in human podocytes

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

Macrophages in neovascular age-related macular degeneration: friends or foes?

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