Overexpression of VEGF in testis and epididymis causes infertility in transgenic mice: Evidence for nonendothelial targets for VEGF

Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability. However, VEGF may also target nonendothelial cell s, as VEGF receptors and responsiveness have been detected for example in m onocytes, and high concentrations of VEGF have been reported in human semen . In this work we present evidence that overexpression of VEGF in the testi s and epididymis of transgenic mice under the mouse mammary tumor virus (MM TV) LTR promoter causes infertility, The testes of the transgenic mice exhi bited spermatogenic arrest and increased capillary density. The ductus epid idymidis was dilated, containing areas of epithelial hyperplasia. The numbe r of subepithelial capillaries in the epididymis was also increased and the se vessels were highly permeable as judged by the detection of extravasated fibrinogen products, Intriguingly, the expression of VEGF receptor-1 (VEGF R-1) was detected in certain spermatogenic cells in addition to vascular en dothelium, 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 resul t from VEGF acting on both endothelial and nonendothelial cells of the male genital tract. Taken together, these findings suggest that the VEGF transg ene has nonendothelial target cells in the testis and that VEGF may regulat e male fertility.