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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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Histological analysis of testes (A–D) and localization of expression of the VEGF transgene and VEGFRs by in situ hybridization (E–L). Comparison of testes from a 6-mo-old MMTV-VEGF transgenic (A and C) and WT control mouse (B and D) indicates that  in the transgenic animals the rete testis (arrows) is dilated and the seminiferous tubules contain vacuoles and disorganized seminiferous  epithelium. The VEGF transgene is expressed in round spermatids (arrowhead) but not in Sertoli cells (arrow) as judged by in situ hybridization with the hVEGF antisense probe (E, dark field; F and G, bright field). Asterisk, lumen of the seminiferous tubule. VEGFR-1  antisense probe recognizes midpachytene spermatocytes and round spermatids in stage VIII seminiferous tubules of the WT mice (K,  dark field; L, bright field) and also Leydig cells in the testis of the MMTV-VEGF mice (H, dark field; I, bright field). The area enclosed  within the rectangle in I is shown at higher magnification in J. Leydig cell (arrow), round spermatid (arrowhead), midpachytene spermatocyte (open arrowhead), and a capillary (asterisk) are indicated. VEGFR-2 signal is detected in the Leydig cells of the MMTV-VEGF  mice (N), whereas the testis of a WT control mouse does not show any hybridization with the VEGFR-2 antisense probe (M). Bars: (A  and B), 500 μm; (C and D) 100 μm; (E, F, H, I, and K–N) 50 μm; (G and J) 10 μm.
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Figure 4: Histological analysis of testes (A–D) and localization of expression of the VEGF transgene and VEGFRs by in situ hybridization (E–L). Comparison of testes from a 6-mo-old MMTV-VEGF transgenic (A and C) and WT control mouse (B and D) indicates that in the transgenic animals the rete testis (arrows) is dilated and the seminiferous tubules contain vacuoles and disorganized seminiferous epithelium. The VEGF transgene is expressed in round spermatids (arrowhead) but not in Sertoli cells (arrow) as judged by in situ hybridization with the hVEGF antisense probe (E, dark field; F and G, bright field). Asterisk, lumen of the seminiferous tubule. VEGFR-1 antisense probe recognizes midpachytene spermatocytes and round spermatids in stage VIII seminiferous tubules of the WT mice (K, dark field; L, bright field) and also Leydig cells in the testis of the MMTV-VEGF mice (H, dark field; I, bright field). The area enclosed within the rectangle in I is shown at higher magnification in J. Leydig cell (arrow), round spermatid (arrowhead), midpachytene spermatocyte (open arrowhead), and a capillary (asterisk) are indicated. VEGFR-2 signal is detected in the Leydig cells of the MMTV-VEGF mice (N), whereas the testis of a WT control mouse does not show any hybridization with the VEGFR-2 antisense probe (M). Bars: (A and B), 500 μm; (C and D) 100 μm; (E, F, H, I, and K–N) 50 μm; (G and J) 10 μm.

Mentions: Histological analysis of the testes of the 6-mo-old MMTV- VEGF mice confirmed that whereas some seminiferous tubules appeared relatively normal, others contained vacuoles and disorganized seminiferous epithelium with few spermatogenic cells (Fig. 4, A–D). The absence of developing spermatids and spermatozoa was clear and numerous degenerating cells were observed in the atrophic tubules. In contrast, the somatic Sertoli and Leydig cells appeared normal. The rete testis was remarkably dilated in the transgenic animals when compared with that of the WT controls. The capillary density was increased by 60 ± 20% as judged by counting of blood vessels in sections stained for the vWF. Also, many of the capillaries of the TG testes were enlarged when compared with the controls.


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)

Histological analysis of testes (A–D) and localization of expression of the VEGF transgene and VEGFRs by in situ hybridization (E–L). Comparison of testes from a 6-mo-old MMTV-VEGF transgenic (A and C) and WT control mouse (B and D) indicates that  in the transgenic animals the rete testis (arrows) is dilated and the seminiferous tubules contain vacuoles and disorganized seminiferous  epithelium. The VEGF transgene is expressed in round spermatids (arrowhead) but not in Sertoli cells (arrow) as judged by in situ hybridization with the hVEGF antisense probe (E, dark field; F and G, bright field). Asterisk, lumen of the seminiferous tubule. VEGFR-1  antisense probe recognizes midpachytene spermatocytes and round spermatids in stage VIII seminiferous tubules of the WT mice (K,  dark field; L, bright field) and also Leydig cells in the testis of the MMTV-VEGF mice (H, dark field; I, bright field). The area enclosed  within the rectangle in I is shown at higher magnification in J. Leydig cell (arrow), round spermatid (arrowhead), midpachytene spermatocyte (open arrowhead), and a capillary (asterisk) are indicated. VEGFR-2 signal is detected in the Leydig cells of the MMTV-VEGF  mice (N), whereas the testis of a WT control mouse does not show any hybridization with the VEGFR-2 antisense probe (M). Bars: (A  and B), 500 μm; (C and D) 100 μm; (E, F, H, I, and K–N) 50 μm; (G and J) 10 μm.
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Figure 4: Histological analysis of testes (A–D) and localization of expression of the VEGF transgene and VEGFRs by in situ hybridization (E–L). Comparison of testes from a 6-mo-old MMTV-VEGF transgenic (A and C) and WT control mouse (B and D) indicates that in the transgenic animals the rete testis (arrows) is dilated and the seminiferous tubules contain vacuoles and disorganized seminiferous epithelium. The VEGF transgene is expressed in round spermatids (arrowhead) but not in Sertoli cells (arrow) as judged by in situ hybridization with the hVEGF antisense probe (E, dark field; F and G, bright field). Asterisk, lumen of the seminiferous tubule. VEGFR-1 antisense probe recognizes midpachytene spermatocytes and round spermatids in stage VIII seminiferous tubules of the WT mice (K, dark field; L, bright field) and also Leydig cells in the testis of the MMTV-VEGF mice (H, dark field; I, bright field). The area enclosed within the rectangle in I is shown at higher magnification in J. Leydig cell (arrow), round spermatid (arrowhead), midpachytene spermatocyte (open arrowhead), and a capillary (asterisk) are indicated. VEGFR-2 signal is detected in the Leydig cells of the MMTV-VEGF mice (N), whereas the testis of a WT control mouse does not show any hybridization with the VEGFR-2 antisense probe (M). Bars: (A and B), 500 μm; (C and D) 100 μm; (E, F, H, I, and K–N) 50 μm; (G and J) 10 μm.
Mentions: Histological analysis of the testes of the 6-mo-old MMTV- VEGF mice confirmed that whereas some seminiferous tubules appeared relatively normal, others contained vacuoles and disorganized seminiferous epithelium with few spermatogenic cells (Fig. 4, A–D). The absence of developing spermatids and spermatozoa was clear and numerous degenerating cells were observed in the atrophic tubules. In contrast, the somatic Sertoli and Leydig cells appeared normal. The rete testis was remarkably dilated in the transgenic animals when compared with that of the WT controls. The capillary density was increased by 60 ± 20% as judged by counting of blood vessels in sections stained for the vWF. Also, many of the capillaries of the TG testes were enlarged when compared with the controls.

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