Autocrine activity of soluble Flt-1 controls endothelial cell function and angiogenesis

被引：53

作者：

Ahmad, Shakil ^{[1
]}

Hewett, Peter W. ^{[2
]}

Al-Ani, Bahjat ^{[2
]}

Sissaoui, Samir ^{[2
]}

Fujisawa, Takeshi ^{[1
]}

Cudmore, Melissa J. ^{[1
]}

Ahmed, Asif ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Univ BHF Ctr Cardiovasc Sci, Queens Med Res Inst, 47 Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland

[2] Univ Birmingham, Coll Med & Dent Sci, Inst Biomed Res, Dept Reprod & Vasc Biol, Birmingham B15 2TT, W Midlands, England

来源：

VASCULAR CELL | 2011年 / 3卷

基金：

英国医学研究理事会;

关键词：

D O I：

10.1186/2045-824X-3-15

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

Background: The negative feedback system is an important physiological regulatory mechanism controlling angiogenesis. Soluble vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), acts as a potent endogenous soluble inhibitor of VEGF- and placenta growth factor (PlGF)-mediated biological function and can also form dominant-negative complexes with competent full-length VEGF receptors. Methods and results: Systemic overexpression of VEGF-A in mice resulted in significantly elevated circulating sFlt-1. In addition, stimulation of human umbilical vein endothelial cells (HUVEC) with VEGF-A, induced a five-fold increase in sFlt-1 mRNA, a time-dependent significant increase in the release of sFlt-1 into the culture medium and activation of the flt-1 gene promoter. This response was dependent on VEGF receptor-2 (VEGFR-2) and phosphoinositide-3'-kinase signalling. siRNA-mediated knockdown of sFlt-1 in HUVEC stimulated the activation of endothelial nitric oxide synthase, increased basal and VEGF-induced cell migration and enhanced endothelial tube formation on growth factor reduced Matrigel. In contrast, adenoviral overexpression of sFlt-1 suppressed phosphorylation of VEGFR-2 at tyrosine 951 and ERK-1/-2 MAPK and reduced HUVEC proliferation. Preeclampsia is associated with elevated placental and systemic sFlt-1. Phosphorylation of VEGFR-2 tyrosine 951 was greatly reduced in placenta from preeclamptic patients compared to gestationally-matched normal placenta. Conclusion: These results show that endothelial sFlt-1 expression is regulated by VEGF and acts as an autocrine regulator of endothelial cell function.

引用

页数：8

共 38 条

[1]

Shweiki D., Itin A., Soffer D., Keshet E., Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis, Nature, 359, pp. 843-845, (1992)

[2]

Dor Y., Camenisch T.D., Itin A., Fishman G.I., McDonald J.A., Carmeliet P., Keshet E., A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects, Development, 128, 9, pp. 1531-1538, (2001)

[3]

Ferrara N., Gerber H.-P., LeCouter J., The biology of VEGF and its receptors, Nature Medicine, 9, 6, pp. 669-676, (2003)

[4]

Giordano F.J., Gerber H.-P., Williams S.-P., Vanbruggen N., Bunting S., Ruiz-Lozano P., Gu Y., Nath A.K., Huang Y., Hickey R., Dalton N., Peterson K.L., Ross Jr. J., Chien K.R., Ferrara N., A cardiac myocyte vascular endothelial growth factor paracrine pathway is required to maintain cardiac function, Proceedings of the National Academy of Sciences of the United States of America, 98, 10, pp. 5780-5785, (2001)

[5]

Oosthuyse B., Moons L., Storkebaum E., Beck H., Nuyens D., Brusselmans K., Dorpe J.V., Hellings P., Gorselink M., Heymans S., Theilmeier G., Dewerchin M., Laudenbach V., Vermylen P., Raat H., Acker T., Vleminckx V., Bosch L.V.D., Cashman N., Fujisawa H., Drost M.R., Sciot R., Bruyninckx F., Hicklin D.J., Ince C., Gressens P., Lupu F., Plate K.H., Robberecht W., Herbert J.-M., Collen D., Carmeliet P., Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter cau

[6]

Storkebaum E., Lambrechts D., Dewerchin M., Moreno-Murciano M.-P., Appelmans S., Oh H., Van Damme P., Rutten B., Man W., De Mol M., Wyns S., Manka D., Vermeulen K., Van Den Bosch L., Mertens N., Schmitz C., Robberecht W., Conway E.M., Collen D., Moons L., Carmeliet P., Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS, Nature Neuroscience, 8, 1, pp. 85-92, (2005)

[7]

Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Eberhardt C., Declercq C., Pawling J., Moons L., Collen D., Risaut W., Nagy A., Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele, Nature, 380, 6573, pp. 435-439, (1996)

[8]

Ferrara N., Carver-Moore K., Chen H., Dowd M., Lu L., O'Shea K.S., Powell-Braxton L., Hillan K.J., Moore M.W., Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene, Nature, 380, 6573, pp. 439-442, (1996)

[9]

Miquerol L., Langille B.L., Nagy A., Embryonic development is disrupted by modest increases in vascular endothelial growth factor gene expression, Development, 127, pp. 3941-3946, (2000)

[10]

Masaki I., Yonemitsu Y., Yamashita A., Sata S., Tanii M., Komori K., Nakagawa K., Hou X., Nagai Y., Hasegawa M., Sugimachi K., Sueishi K., Angiogenic gene therapy for experimental critical limb ischemia: Acceleration of limb loss by overexpression of vascular endothelial growth factor 165 but not of fibroblast growth factor-2, Circulation Research, 90, 9, pp. 966-973, (2002)

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