Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis

Xia, Yifan; Li, Baosheng; Hylton, Donna; Detmar, Michael; Yancopouloš, George D.; Rudge, John S.

doi:10.1182/blood-2002-12-3793

Cited by 329 publications

(330 citation statements)

References 53 publications

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“…The generation of K14-VEGF-A Tg mice that express mouse VEGF-A164 under control of the K14 promoter, of K14-VEGF-C Tg mice that express human VEGF-C, and of K14-VEGF-D Tg mice that express mouse VEGF-D has been described previously Detmar et al, 1998;Xia et al, 2003;Haiko et al, 2008). K14-VEGF-A, K14-VEGF-C, and K14-VEGF-D Tg mice (all FVB genetic background) were bred and housed in the animal facility of ETH Zurich.…”

Section: Methodsmentioning

confidence: 99%

“…In these conditions, levels of vascular endothelial growth factor (VEGF) A are elevated in the inflamed tissue (Detmar et al, 1994;Koch et al, 1994;Kanazawa et al, 2001). Homozygous keratin 14 (K14) VEGF-A transgenic (Tg) mice, which overexpress mouse VEGF-A 164 in the epidermis, spontaneously develop a chronic inflammatory skin disease with many features of human psoriasis at an age of 6 mo (Xia et al, 2003).…”

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confidence: 99%

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Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Huggenberger¹,

Ullmann²,

Proulx³

et al. 2010

J Cell Biol

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The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation

Huggenberger¹,

Ullmann²,

Proulx³

et al. 2010

J Cell Biol

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“…VEGF-B transgenic expression in different organs induces no or minimum angiogenesis. Transgenic expression of all the other VEGF family members, such as VEGF-A, [38][39][40] PlGF, 41 VEGF-C, 42 VEGF-D 43 or VEGF-E, 44 induced either angiogenesis or lymphangiogenesis. VEGF-B is the only member of the VEGF family, transgenic overexpression of which in different organs did not induce angiogenesis or lymphangiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Vegf-B

Lee

Tang

et al. 2009

Cell Adhesion & Migration

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Despite its early discovery and high sequence homology to the other VEGF family members, the biological function of VEGF-B remained debatable for a long time, and VEGF-B has received little attention from the field thus far. Recently, we and others have found that (1) VEGF-B is a potent survival factor for different types of cells by inhibiting apoptosis via suppressing the expression of BH3-only protein and other apoptotic/cell deathrelated genes. (2) VEGF-B has a negligible role in inducing blood vessel growth in most organs. Instead, it is critically required for blood vessel survival. VEGF-B targeting inhibited pathological angiogenesis by abolishing blood vessel survival in different animal models. (3) Using different types of neuro-injury and neurodegenerative disease models, VEGF-B treatment protected endangered neurons from apoptosis without inducing undesired blood vessel growth or permeability. Thus, VEGF-B is the first member of the VEGF family that has a potent survival/antiapoptotic effect, while lacking a general angiogenic activity. Our work thus advocates that the major function of VEGF-B is to act as a "survival," rather than an "angiogenic" factor and implicates a therapeutic potential of VEGF-B in treating different types of vascular and neurodegenerative diseases.

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“…29 However, mVEGF-164 induced the formation of irregular, tortuous blood vessels as already described [55][56][57] and of lacunaelike structures in the tumor tissue. Angiogenesis was similarly accelerated and enhanced in the mVEGF-164 plus hPDGF-B mixed surface transplants, but blood vessel growth was more directional and the tumor tissue appeared more compact.…”

Section: Discussionmentioning

confidence: 99%