Vascular endothelial growth factor and its receptors in normal human testicular tissue

Ergün, Süleyman; Kilic, Nerbil; Fiedler, Walter; Mukhopadhyay, Amal K.

doi:10.1016/s0303-7207(97)00082-8

Cited by 129 publications

(110 citation statements)

References 48 publications

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“…With KDR, the reverse was true, with very strong expression by epithelial cells. This observation has precedent, with the differential expression of VEGF receptors having been described in normal human testes where a paracrine mitogenic and angiogenic role has been proposed (Ergun et al, 1997). Flt-1 has a higher affinity for VEGF than KDR and each have different signalling pathways (Waltenberger et al, 1994;Seetharam et al, 1995).…”

Section: Discussionmentioning

confidence: 97%

“…With the exception of ovarian carcinoma cells (Boocock et al, 1995), melanoma (Gitay-Goran et al, 1993), placental trophoblasts (Charnock-Jones et al, 1994), human testes (Ergun et al, 1997) and monocytes which express Flt-1 but not KDR (Hewett et al, 1996), VEGF receptors are expressed almost exclusively by endothelial cells involved with tumour neovascularization (Jakeman et al, 1992;Hewett and Murray, 1996). Because of the nature of our cell separation prcedure combined with the high sensitivity of the PCR technique, it was possible that we may have been amplifying Flt-1 and KDR message from occult endothelial cells rather than epithelial cells or fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

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Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours

Speirs

Atkin

1999

Br J Cancer

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Production of vascular endothelial growth factor (VEGF) and expression of its receptors Flt-1 and KDR was determined in primary cultures of separated epithelial and stromal-enriched cultures derived from ten primary human breast carcinomas. By enzyme-linked immunosorbent assay, epithelial cells produced a mean VEGF of 33 ± 7 pg ml −1 μg −1 RNA (range 11–70). Stromal cells produced similar levels, with a mean of 48 ± 11 pg ml −1 μg −1 RNA (range 7–92). This was significantly greater than the amount produced by similar cultures derived from normal breast tissue (epithelial mean 19 ± 5 pg ml −1 μg −1 RNA, range 9–34, P < 0.05 vs tumour epithelial culture; stromal mean 26 ± 8 pg ml −1 μg −1 RNA, range 3–56). Flt-1 and KDR receptors were analysed by semi-quantitative reverse transcription polymerase chain reaction. Flt-1 was expressed by four of six epithelial and five of six stromal cultures. When expressed by both cell types, Flt-1 appeared to be significantly more abundant on stromal cells compared with epithelial cultures. Only a single tumour, a lobular carcinoma, failed to express Flt-1 on either cell type. With KDR, the reverse was true with constitutive expression of this receptor by epithelial cultures and zero or reduced (3/6) expression by stromal cultures. Differences in the expression pattern of VEGF receptors may reflect a differential response to VEGF by specific cell types. Thus, production of VEGF and expression of VEGF receptors Flt-1 and KDR by breast cancer epithelial and stromal cells suggests that VEGF may fulfil not only an angiogenic role, but also play a fundamental role as an autocrine/paracrine regulator in breast cancer, thereby facilitating tumour proliferation and subsequent invasion. © 1999 Cancer Research Campaign

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours

Speirs

Atkin

1999

Br J Cancer

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“…Based on the data presented here, we hypothesize that proliferating undifferentiated germ cells may produce VEGF in response to local hypoxia and oxidative stress to prevent apoptosis in these cells preceding the onset of puberty. Accordingly, testicular germ cells of several species express KDR and FLT1 (Ergun et al 1997, Nalbandian et al 2003, Rudolfsson et al 2004, and although these receptors are expressed in endothelial cells, no active angiogenesis takes place within the postnatal testis. VEGF synthesis by Leydig cells is stimulated in response to hCG/LH (Rudolfsson et al 2004), and FSH triggers Sertoli cell production of VEGF in the adult testis (Marti & Risau 1998, Liu & Yang 2004, Reisinger et al 2007.…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of reports suggest that VEGFA has direct effects on nonvascular cells including neuronal cells (Marti & Risau 1998, Wada et al 2006, Nishijima et al 2007), muscle cells (Germani et al 2003, Bryan et al 2008, and granulosa cells (Greenaway et al 2004). Data also suggest potential functional roles for VEGFA in the postnatal testis, as KDR and FLT1 are expressed in testicular germ cells in humans (Ergun et al 1997), rats (Rudolfsson et al 2004), and mice (Nalbandian et al 2003), while somatic Sertoli and Leydig cells produce VEGFA (Liu & Yang 2004). Two studies have shown that overexpression of VEGFA-120 and VEGFA-165 causes detrimental effects on male fertility in transgenic mice (Korpelainen et al 1998, Huminiecki et al 2001.…”

Section: Introductionmentioning

confidence: 99%

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

Caires

Avila²,

McLean

2009

Reproduction

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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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“…In rodents, Leydig and Sertoli cells produce VEGF, and Leydig expression is stimulated by human chorionic gonadotropin (hCG) treatment (Nalbandian et al 2003, Rudolfsson et al 2004. In mice and human testes, Leydig cells express the VEGF receptors KDR and FLT1 (Ergun et al 1997, Korpelainen et al 1998. We have shown that VEGF treatment of bovine testis tissue increases germ cell differentiation resulting in more sperm produced in testis tissue grafts (Schmidt et al 2006).…”

Section: Crosstalk and Gdnf-independent Signaling In Sscsmentioning

confidence: 98%

Maintaining the male germline: regulation of spermatogonial stem cells

Caires

Broady²,

McLean

2010

Journal of Endocrinology

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Spermatogonial stem cells (SSCs) are a self-renewing population of adult stem cells capable of producing progeny cells for sperm production throughout the life of the male. Regulation of the SSC population includes establishment and maintenance of a niche microenvironment in the seminiferous tubules of the testis. Signaling from somatic cells within the niche determines the fate of SSCs by either supporting self-renewal or initiating differentiation leading to meiotic entry and production of spermatozoa. Despite the importance of these processes, little is known about the biochemical and cellular mechanisms that govern SSC fate and identity. This review discusses research findings regarding systemic, endocrine, and local cues that stimulate somatic niche cells to produce factors that contribute to the homeostasis of SSCs in mammals. In addition to their importance for male fertility, SSCs represent a model for the investigation of adult stem cells because they can be maintained in culture, and the presence, proliferation, or loss of SSCs in a cell population can be determined with the use of a transplantation assay. Defining the mechanisms that regulate the self-renewal and differentiation of SSCs will fundamentally improve the understanding of male fertility and provide information about the regulation of adult stem cells in other tissues.

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Vascular endothelial growth factor and its receptors in normal human testicular tissue

Cited by 129 publications

References 48 publications

Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours

Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours

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

Maintaining the male germline: regulation of spermatogonial stem cells

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