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© The Rockefeller University Press, 0021-9525/1998//1705 $5.00
The Journal of Cell Biology, Volume 143, Number 6, , 1998 1705-1712

Article

Overexpression of VEGF in Testis and Epididymis Causes Infertility in Transgenic Mice: Evidence for Nonendothelial Targets for VEGF



Eija I. Korpelainen*, Marika J. Karkkainen*, Auri Tenhunen*, Merja Lakso{ddagger}, Heikki Rauvala{ddagger}, Matti Vierula§, Martti Parvinen§, and Kari Alitalo*

* Molecular/Cancer Biology Laboratory, Haartman Institute and {ddagger} Biotechnology Institute, University of Helsinki, 00014 Helsinki, Finland; and § Institute of Biomedicine, Department of Anatomy, University of Turku, 20520 Turku, Finland

Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability. However, VEGF may also target nonendothelial cells, as VEGF receptors and responsiveness have been detected for example in monocytes, and high concentrations of VEGF have been reported in human semen. In this work we present evidence that overexpression of VEGF in the testis and epididymis of transgenic mice under the mouse mammary tumor virus (MMTV) LTR promoter causes infertility. The testes of the transgenic mice exhibited spermatogenic arrest and increased capillary density. The ductus epididymidis was dilated, containing areas of epithelial hyperplasia. The number of subepithelial capillaries in the epididymis was also increased and these vessels were highly permeable as judged by the detection of extravasated fibrinogen products. Intriguingly, the expression of VEGF receptor-1 (VEGFR-1) was detected in certain spermatogenic cells in addition to vascular endothelium, and both VEGFR-1 and VEGFR-2 were also found in the Leydig cells of the testis. The infertility of the MMTV-VEGF male mice could thus result from VEGF acting on both endothelial and nonendothelial cells of the male genital tract. Taken together, these findings suggest that the VEGF transgene has nonendothelial target cells in the testis and that VEGF may regulate male fertility.

Key Words: VEGF • VEGF receptors • spermato-genesis • fertility • transgenic mice

Abbreviations used in this paper: MMTV, mouse mammary tumor virus; RT, room temperature; TG, transgenic; VEGF, vascular endothelial growth factor; VEGFR-1, VEGF receptor-1; vWF, von Willebrand factor; WT, wild-type.

E.I. Korpelainen and M.J. Karkkainen contributed equally to this work.


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