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

Korpelainen EI, Karkkainen MJ, Tenhunen A, Lakso M, Rauvala H, Vierula M, Parvinen M, Alitalo K - J. Cell Biol. (1998)

Bottom Line: Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular/Cancer Biology Laboratory, Haartman Institute, Helsinki, Finland.

ABSTRACT
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.

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Related in: MedlinePlus

Expression of the VEGF transgene mRNA in the epididymis and testis. Total RNA was prepared from the testis, epididymis, and prostate of MMTV-VEGF transgenic mice and WT  control mice and then 10-μg samples were analyzed by Northern  blotting using the hVEGF-165 cDNA fragment as a probe (top).  Mammary gland (MG) RNA of MMTV-VEGF female mice was  used as a positive control. Signals corresponding to the VEGF  transgene mRNA (TG VEGF) and the endogenous mouse  VEGF mRNA are shown. The filter was stripped and reprobed  for GAPDH to check RNA loading (bottom).
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Figure 1: Expression of the VEGF transgene mRNA in the epididymis and testis. Total RNA was prepared from the testis, epididymis, and prostate of MMTV-VEGF transgenic mice and WT control mice and then 10-μg samples were analyzed by Northern blotting using the hVEGF-165 cDNA fragment as a probe (top). Mammary gland (MG) RNA of MMTV-VEGF female mice was used as a positive control. Signals corresponding to the VEGF transgene mRNA (TG VEGF) and the endogenous mouse VEGF mRNA are shown. The filter was stripped and reprobed for GAPDH to check RNA loading (bottom).

Mentions: To study the effect of VEGF overexpression in transgenic mice, the cDNA coding for the 165-amino acid isoform of hVEGF was expressed under the MMTV promoter. Nine different MMTV-VEGF transgenic lines were obtained, with copy numbers ranging from <1 (mosaic) to 18 as judged by Southern blotting (data not shown). The MMTV- VEGF mice appeared healthy and did not exhibit any macroscopic physical aberrations or reduction in body weight. To confirm transgene expression, RNA samples from different tissues were analyzed by Northern blotting (Fig. 1). As expected, high levels of the VEGF transgene mRNA were detected in mammary glands of lactating females. Interestingly, the transgene was expressed at comparable levels in the epididymis and to a lesser extent in the testis, whereas no expression was detected in the prostate (Fig. 1) or seminal vesicle (data not shown).


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

Korpelainen EI, Karkkainen MJ, Tenhunen A, Lakso M, Rauvala H, Vierula M, Parvinen M, Alitalo K - J. Cell Biol. (1998)

Expression of the VEGF transgene mRNA in the epididymis and testis. Total RNA was prepared from the testis, epididymis, and prostate of MMTV-VEGF transgenic mice and WT  control mice and then 10-μg samples were analyzed by Northern  blotting using the hVEGF-165 cDNA fragment as a probe (top).  Mammary gland (MG) RNA of MMTV-VEGF female mice was  used as a positive control. Signals corresponding to the VEGF  transgene mRNA (TG VEGF) and the endogenous mouse  VEGF mRNA are shown. The filter was stripped and reprobed  for GAPDH to check RNA loading (bottom).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132976&req=5

Figure 1: Expression of the VEGF transgene mRNA in the epididymis and testis. Total RNA was prepared from the testis, epididymis, and prostate of MMTV-VEGF transgenic mice and WT control mice and then 10-μg samples were analyzed by Northern blotting using the hVEGF-165 cDNA fragment as a probe (top). Mammary gland (MG) RNA of MMTV-VEGF female mice was used as a positive control. Signals corresponding to the VEGF transgene mRNA (TG VEGF) and the endogenous mouse VEGF mRNA are shown. The filter was stripped and reprobed for GAPDH to check RNA loading (bottom).
Mentions: To study the effect of VEGF overexpression in transgenic mice, the cDNA coding for the 165-amino acid isoform of hVEGF was expressed under the MMTV promoter. Nine different MMTV-VEGF transgenic lines were obtained, with copy numbers ranging from <1 (mosaic) to 18 as judged by Southern blotting (data not shown). The MMTV- VEGF mice appeared healthy and did not exhibit any macroscopic physical aberrations or reduction in body weight. To confirm transgene expression, RNA samples from different tissues were analyzed by Northern blotting (Fig. 1). As expected, high levels of the VEGF transgene mRNA were detected in mammary glands of lactating females. Interestingly, the transgene was expressed at comparable levels in the epididymis and to a lesser extent in the testis, whereas no expression was detected in the prostate (Fig. 1) or seminal vesicle (data not shown).

Bottom Line: Vascular endothelial growth factor (VEGF) is a key regulator of endothelial growth and permeability.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular/Cancer Biology Laboratory, Haartman Institute, Helsinki, Finland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus