Vascular endothelial growth factor A: just one of multiple mechanisms for sex-specific vascular development within the testis?

Testis development from an indifferent gonad is a critical step in embryogenesis. A hallmark of testis differentiation is sex-specific vascularization that occurs as endothelial cells migrate from the adjacent mesonephros into the testis to surround Sertoli-germ cell aggregates and induce seminiferous cord formation. Manyin vitroexperiments have demonstrated that vascular endothelial growth factor A (VEGFA) is a critical regulator of this process. Both inhibitors to VEGFA signal transduction and excess VEGFA isoforms in testis organ cultures impaired vascular development and seminiferous cord formation. However,in vivomodels using mice which selectively eliminated all VEGFA isoforms: in Sertoli and germ cells (pDmrt1-Cre;Vegfa−/−); Sertoli and Leydig cells (Amhr2-Cre;Vegfa−/−) or Sertoli cells (Amh-Cre;Vegfa−/−andSry-Cre;Vegfa−/−) displayed testes with observably normal cords and vasculature at postnatal day 0 and onwards. Embryonic testis development may be delayed in these mice; however, the postnatal data indicate that VEGFA isoforms secreted from Sertoli, Leydig or germ cells are not required for testis morphogenesis within the mouse. AVegfasignal transduction array was employed on postnatal testes fromSry-Cre;Vegfa−/−versus controls.Ptgs1(Cox1) was the only upregulated gene (fivefold). COX1 stimulates angiogenesis and upregulates, VEGFA, Prostaglandin E2 (PGE2) and PGD2. Thus, other gene pathways may compensate for VEGFA loss, similar to multiple independent mechanisms to maintain SOX9 expression. Multiple independent mechanism that induce vascular development in the testis may contribute to and safeguard the sex-specific vasculature development responsible for inducing seminiferous cord formation, thus ensuring appropriate testis morphogenesis in the male.

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Regulation of vascular endothelial growth factor expression in human endometrium by steroids and hypoxia: In vitro and in vivo studies

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86195-3 ◽

1998 ◽

Vol 5 (1) ◽

pp. 69A-69A

Author(s):

A SHARKEY ◽

D CHARNOCKJONES ◽

K DAY ◽

H SOWTER ◽

L SVENSSON ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Human Endometrium ◽

In Vivo Studies ◽

Vascular Endothelial ◽

Factor Expression ◽

Growth Factor Expression ◽

Endothelial Growth Factor

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Transgenic Overexpression of Vascular Endothelial Growth Factor-B Isoforms by Endothelial Cells Potentiates Postnatal Vessel Growth In Vivo and In Vitro

Circulation Research ◽

10.1161/01.res.0000182631.33638.77 ◽

2005 ◽

Vol 97 (6) ◽

Cited By ~ 38

Author(s):

Arne W. Mould ◽

Sonia A. Greco ◽

Marian M. Cahill ◽

Ian D. Tonks ◽

Daniela Bellomo ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Endothelial Cells ◽

Growth Factor ◽

Vascular Endothelial ◽

Factor B ◽

Vessel Growth ◽

Endothelial Growth Factor

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Regulation of Vascular Endothelial Growth Factor by Tamoxifen in vitro and in vivo

Gynecologic and Obstetric Investigation ◽

10.1159/000070190 ◽

2003 ◽

Vol 55 (2) ◽

pp. 119-124 ◽

Cited By ~ 3

Author(s):

Michael D. Mueller ◽

Elizabeth A. Pritts ◽

Charles J. Zaloudek ◽

Ekkehard Dreher ◽

Robert N. Taylor

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Vascular Endothelial ◽

Endothelial Growth Factor

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Total saponins from Albizia julibrissin inhibit vascular endothelial growth factor-mediated angiogenesis in vitro and in vivo

Molecular Medicine Reports ◽

10.3892/mmr.2015.3228 ◽

2015 ◽

Vol 11 (5) ◽

pp. 3405-3413 ◽

Cited By ~ 9

Author(s):

WEIWEI CAI ◽

YUE LI ◽

QINGQING YI ◽

FENGSHAN XIE ◽

BIN DU ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Vascular Endothelial ◽

Albizia Julibrissin ◽

Endothelial Growth Factor

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Vascular endothelial growth factor regulates germ cell survival during establishment of spermatogenesis in the bovine testis

Reproduction ◽

10.1530/rep-09-0020 ◽

2009 ◽

Vol 138 (4) ◽

pp. 667-677 ◽

Cited By ~ 47

Author(s):

Kyle C Caires ◽

Jeanene de Avila ◽

Derek J McLean

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Germ Cell ◽

Cell Survival ◽

Germ Cells ◽

Pcr Analysis ◽

Vascular Endothelial ◽

Endothelial Growth Factor ◽

Testis Tissue

Vascular endothelial growth factor-A (VEGFA) is a hypoxia-inducible peptide essential for angiogenesis and targets nonvascular cells in a variety of tissues and cell types. The objective of the current study was to determine the function of VEGF during testis development in bulls. We used an explant tissue culture and treatment approach to test the hypothesis that VEGFA-164 could regulate the biological activity of bovine germ cells. We demonstrate that VEGFA, KDR, and FLT1 proteins are expressed in germ and somatic cells in the bovine testis. Treatment of bovine testis tissue with VEGFA in vitro resulted in significantly more germ cells following 5 days of culture when compared with controls. Quantitative real-time RT-PCR analysis determined that VEGF treatment stimulated an intracellular response that prevents germ cell death in bovine testis tissue explants, as indicated by increased expression of BCL2 relative to BAX and decreased expression of BNIP3 at 3, 6, and 24 h during culture. Blocking VEGF activity in vitro using antisera against KDR and VEGF significantly reduced the number of germ cells in VEGF-treated testis tissue to control levels at 120 h. Testis grafting provided in vivo evidence that bovine testis tissue treated with VEGFA for 5 days in culture contained significantly more differentiating germ cells compared with controls. These findings support the conclusion that VEGF supports germ cell survival and sperm production in bulls.

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Vascular Endothelial Growth Factor Inhibits the Development of Dendritic Cells and Dramatically Affects the Differentiation of Multiple Hematopoietic Lineages In Vivo

Blood ◽

10.1182/blood.v92.11.4150 ◽

1998 ◽

Vol 92 (11) ◽

pp. 4150-4166 ◽

Cited By ~ 624

Author(s):

Dmitry Gabrilovich ◽

Tadao Ishida ◽

Tsunehiro Oyama ◽

Sophia Ran ◽

Vladimir Kravtsov ◽

...

Keyword(s):

Stem Cells ◽

Vascular Endothelial Growth Factor ◽

Dendritic Cells ◽

Growth Factor ◽

System Control ◽

Vascular Endothelial ◽

Almost All ◽

Endothelial Growth Factor

Abstract Defective function of dendritic cells (DC) in cancer has been recently described and may represent one of the mechanisms of tumor evasion from immune system control. We have previously shown in vitro that vascular endothelial growth factor (VEGF), produced by almost all tumors, is one of the tumor-derived factors responsible for the defective function of these cells. In this study, we investigated whether in vivo infusion of recombinant VEGF could reproduce the observed DC dysfunction. Continuous VEGF infusion, at rates as low as 50 ng/h (resulting in serum VEGF concentrations of 120 to 160 pg/mL), resulted in a dramatic inhibition of dendritic cell development, associated with an increase in the production of B cells and immature Gr-1+ myeloid cells. Infusion of VEGF was associated with inhibition of the activity of the transcription factor NF-κB in bone marrow progenitor cells. Experiments in vitro showed that VEGF itself, and not factors released by VEGF-activated endothelial cells, affected polypotent stem cells resulting in the observed abnormal hematopoiesis. These data suggest that VEGF, at pathologically relevant concentrations in vivo, may exert effects on pluripotent stem cells that result in blocked DC development as well as affect many other hematopoietic lineages.

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