Soluble neuropilin targeted to the skin inhibits vascular permeability

被引：32

作者：

Mamluk R. ^{[1
,2
,5
]}

Klagsbrun M. ^{[1
,2
,3
,6
]}

Detmar M. ^{[4
]}

Bielenberg D.R. ^{[1
,2
]}

机构：

[1] Vascular Biology Program, Children's Hospital and Harvard Medical School, Karp Family Research Building, Boston, MA

[2] Departments of Surgery, Children's Hospital and Harvard Medical School, Karp Family Research Building, Boston, MA

[3] Departments of Pathology, Children's Hospital and Harvard Medical School, Karp Family Research Building, Boston, MA

[4] Department of Dermatology, Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA

[5] Compound Therapeutics, Waltham, MA

[6] Children's Hospital, Department of Surgery, Vascular Biology Program, Boston, MA 02115, One Blackfan Circle

来源：

Angiogenesis | 2005年 / 8卷 / 3期

基金：

美国国家卫生研究院;

关键词：

Delayed-type hypersensitivity; Endothelial cells; Keratin; 14; Permeability; Soluble neuropilin; VEGF;

D O I：

10.1007/s10456-005-9009-6

中图分类号：

学科分类号：

摘要：

Neuropilin 1 (NRP1) is a co-receptor for vascular endothelial growth factor (VEGF165), an inducer of vascular permeability and angiogenesis. Numerous physiological factors enhance VEGF expression and function but only a few have been shown to be negative regulators. Previously, we have shown that the naturally occurring soluble form of NRP1 (sNRP1) inhibits binding of VEGF165 to endothelial cells in vitro and impairs tumor growth in vivo. To investigate the role of sNRP1 in the regulation of vascular development and function, sNRP1 expression was targeted to the skin, where it is not normally expressed, using a keratin 14 (K14) promoter expression construct. K14-sNRP1 transgenic mice displayed normal skin architecture with a subtle abnormal vascular phenotype. While the overall number of skin blood vessels remained unchanged, the lumen size of smooth muscle-associated dermal vessels was reduced. K14-sNRP1 mice had reduced vascular permeability in response to VEGF165, but also to VEGF121 and platelet activating factor, suggesting that the lack of permeability was not solely due to the sequestration of VEGF. sNRP1 also reversed the increase in inflammation and edema induced by transgenic VEGF overexpression in cutaneous delayed-type hypersensitivity reactions. In summary, sNRP1 appears to primarily regulate vessel permeability while its effect on physiological angiogenesis is less evident in this model. © Springer 2005.

引用

页码：217 / 227

页数：10

共 37 条

[11] Gagnon M.L., Bielenberg D.R., Gechtman Z., Et al., Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity, Proc Natl Acad Sci, 97, 6, pp. 2573-2578, (2000)
[12] Rossignol M., Gagnon M.L., Klagsbrun M., Genomic organization of human neuropilin-1 and neuropilin-2 genes: Identification and distribution of splice variants and soluble isoforms, Genomics, 70, 2, pp. 211-222, (2000)
[13] Mamluk R., Gechtman Z., Kutcher M.E., Et al., Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain, J Biol Chem, 277, 27, pp. 24818-24825, (2002)
[14] Yamada Y., Takakura N., Yasue H., Et al., Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis, Blood, 97, 6, pp. 1671-1678, (2001)
[15] Kishimoto J., Ehama R., Ge Y., Et al., In vivo detection of human vascular endothelial growth factor promoter activity in transgenic mouse skin, Am J Pathol, 157, 1, pp. 103-110, (2000)
[16] Detmar M., Yeo K.T., Nagy J.A., Et al., Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells, J Invest Dermatol, 105, 1, pp. 44-50, (1995)
[17] Detmar M., Brown L.F., Schon M.P., Et al., Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice, J Invest Dermatol, 111, 1, pp. 1-6, (1998)
[18] Bielenberg D.R., McCarty M.F., Bucana C.D., Et al., Expression of interferon-beta is associated with growth arrest of murine and human epidermal cells, J Invest Dermatol, 112, 5, pp. 802-809, (1999)
[19] Oura H., Bertoncini J., Velasco P., Et al., A critical role of placental growth factor in the induction of inflammation and edema formation, Blood, 101, 2, pp. 560-567, (2003)
[20] Gad S.C., Dunn B.J., Dobbs D.W., Et al., Development and validation of an alternative dermal sensitization test: The mouse ear swelling test (MEST), Toxicol Appl Pharmacol, 84, 1, pp. 93-114, (1986)

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