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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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Aberrant spermatogenesis in MMTV-VEGF  transgenic mice. Transillumination analysis of seminiferous tubules dissected  from the testis of a 6-mo-old  MMTV-VEGF mouse (top)  indicated that whereas some  tubules appeared normal (N),  the majority were homogeneously pale (P), lacking the  normal spermatogenic wave,  and some contained heavily  light absorbing hard material  (H). Squash preparation of  the pale segment (bottom)  shows that the spermatogenesis is interrupted at the elongation phase of the spermatids. Normal meiotic cell (M), step 9 spermatid (S), and apoptotic spermatocyte (A) are indicated. Bars: (top) 0.25 mm; (bottom) 10 μm.
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Figure 3: Aberrant spermatogenesis in MMTV-VEGF transgenic mice. Transillumination analysis of seminiferous tubules dissected from the testis of a 6-mo-old MMTV-VEGF mouse (top) indicated that whereas some tubules appeared normal (N), the majority were homogeneously pale (P), lacking the normal spermatogenic wave, and some contained heavily light absorbing hard material (H). Squash preparation of the pale segment (bottom) shows that the spermatogenesis is interrupted at the elongation phase of the spermatids. Normal meiotic cell (M), step 9 spermatid (S), and apoptotic spermatocyte (A) are indicated. Bars: (top) 0.25 mm; (bottom) 10 μm.

Mentions: Because of the lack of spermatozoa in the ductus epididymidis, the testes of MMTV-VEGF males were analyzed in detail. The seminiferous tubules were first examined in freshly isolated living condition by transillumination. Since tubular segments containing maturation phase spermatids appear dark due to the DNA compaction, this technique can be used to obtain a rapid overview of the spermatogenic development (25). Although the MMTV-VEGF mice had some normal-looking tubules, the majority of the tubules appeared homogeneously pale, lacking the normal spermatogenic wave (Fig. 3, top). Squash preparations of these segments demonstrated that spermatogenesis was interrupted at the elongation phase of the spermatids (Fig. 3, bottom). Neither elongated spermatids or spermatozoa were observed, but somatic Sertoli cells, spermatogonia, meiotic cells, and round spermatids appeared normal. We also observed many phase-negative cellular spheres, which have been shown to correspond to apoptotic bodies (16). Some tubules contained heavily light absorbing material that appeared to have a very hard consistency, which did not permit a normal analysis of living cells in the squash preparations (Fig. 3, top).


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)

Aberrant spermatogenesis in MMTV-VEGF  transgenic mice. Transillumination analysis of seminiferous tubules dissected  from the testis of a 6-mo-old  MMTV-VEGF mouse (top)  indicated that whereas some  tubules appeared normal (N),  the majority were homogeneously pale (P), lacking the  normal spermatogenic wave,  and some contained heavily  light absorbing hard material  (H). Squash preparation of  the pale segment (bottom)  shows that the spermatogenesis is interrupted at the elongation phase of the spermatids. Normal meiotic cell (M), step 9 spermatid (S), and apoptotic spermatocyte (A) are indicated. Bars: (top) 0.25 mm; (bottom) 10 μm.
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Related In: Results  -  Collection

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

Figure 3: Aberrant spermatogenesis in MMTV-VEGF transgenic mice. Transillumination analysis of seminiferous tubules dissected from the testis of a 6-mo-old MMTV-VEGF mouse (top) indicated that whereas some tubules appeared normal (N), the majority were homogeneously pale (P), lacking the normal spermatogenic wave, and some contained heavily light absorbing hard material (H). Squash preparation of the pale segment (bottom) shows that the spermatogenesis is interrupted at the elongation phase of the spermatids. Normal meiotic cell (M), step 9 spermatid (S), and apoptotic spermatocyte (A) are indicated. Bars: (top) 0.25 mm; (bottom) 10 μm.
Mentions: Because of the lack of spermatozoa in the ductus epididymidis, the testes of MMTV-VEGF males were analyzed in detail. The seminiferous tubules were first examined in freshly isolated living condition by transillumination. Since tubular segments containing maturation phase spermatids appear dark due to the DNA compaction, this technique can be used to obtain a rapid overview of the spermatogenic development (25). Although the MMTV-VEGF mice had some normal-looking tubules, the majority of the tubules appeared homogeneously pale, lacking the normal spermatogenic wave (Fig. 3, top). Squash preparations of these segments demonstrated that spermatogenesis was interrupted at the elongation phase of the spermatids (Fig. 3, bottom). Neither elongated spermatids or spermatozoa were observed, but somatic Sertoli cells, spermatogonia, meiotic cells, and round spermatids appeared normal. We also observed many phase-negative cellular spheres, which have been shown to correspond to apoptotic bodies (16). Some tubules contained heavily light absorbing material that appeared to have a very hard consistency, which did not permit a normal analysis of living cells in the squash preparations (Fig. 3, top).

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