Vascular endothelial growth factor and kinase domain region receptor are involved in both seminiferous cord formation and vascular development during testis morphogenesis in the rat

Rebecca C. Bott, Ryann M. McFee, Debra T. Clopton, Candice Toombs, Andrea S. Cupp

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Morphological male sex determination is dependent on migration of endothelial and preperitubular cells from the adjacent mesonephros into the developing testis. Our hypothesis is that VEGFA and its receptor KDR are necessary for both testicular cord formation and neovascularization. The Vegfa gene has 8 exons with many splice variants. Vegfa120, Vegfa164, and Vegfa188 mRNA isoforms were detected on Embryonic Day (E) 13.5 (plug date = E0) in the rat. Vegfa120, Vegfa144, Vegfa164, Vegfa188, and Vegfa205 mRNA were detected at E18 and Postnatal Day 3 (P3). Kdr mRNA was present on E13.5, whereas Fms-like tyrosine kinase 1 receptor (Flt1) mRNA was not detected until E18. VEGFA protein was localized to Sertoli cells at cord formation and KDR to germ and interstitial cells. The VEGFA signaling inhibitors SU1498 (40 μM) and VEGFR-TKI (8 μM) inhibited cord formation in E13 testis cultures with 90% reduced vascular density (P < 0.01) in VEGFR-TKI-treated organs. Furthermore, Je-11 (10 μM), an antagonist to VEGFA, also perturbed cord formation and inhibited vascular density by more than 50% (P < 0.01). To determine signal transduction pathways involved in VEGFA's regulation of testis morphogenesis, E13 testis were treated with LY 294002 (15 μM), a phosphoinositide 3-kinase (P13K) pathway inhibitor, resulting in inhibition of both vascular density (46%) and cord formation. Thus, we support our hypothesis and conclude that VEGFA, secreted by the Sertoli cell, is involved in both neovascularization and cord formation and potentially acts through the P13K pathway during testis morphogenesis to elicit its effects.

Original languageEnglish (US)
Pages (from-to)56-67
Number of pages12
JournalBiology of reproduction
Volume75
Issue number1
DOIs
StatePublished - Jul 1 2006

Fingerprint

Morphogenesis
Vascular Endothelial Growth Factor A
Blood Vessels
Testis
Phosphotransferases
Sertoli Cells
Messenger RNA
Mesonephros
RNA Isoforms
Vascular Endothelial Growth Factor Receptor-1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
1-Phosphatidylinositol 4-Kinase
Receptor Protein-Tyrosine Kinases
Germ Cells
Exons
Signal Transduction
Endothelial Cells
Genes
Proteins

Keywords

  • Growth factors
  • Sertoli cells
  • Testis

ASJC Scopus subject areas

  • Reproductive Medicine
  • Cell Biology

Cite this

Vascular endothelial growth factor and kinase domain region receptor are involved in both seminiferous cord formation and vascular development during testis morphogenesis in the rat. / Bott, Rebecca C.; McFee, Ryann M.; Clopton, Debra T.; Toombs, Candice; Cupp, Andrea S.

In: Biology of reproduction, Vol. 75, No. 1, 01.07.2006, p. 56-67.

Research output: Contribution to journalArticle

@article{03c778e25aa148fb94f2cc74ba230b38,
title = "Vascular endothelial growth factor and kinase domain region receptor are involved in both seminiferous cord formation and vascular development during testis morphogenesis in the rat",
abstract = "Morphological male sex determination is dependent on migration of endothelial and preperitubular cells from the adjacent mesonephros into the developing testis. Our hypothesis is that VEGFA and its receptor KDR are necessary for both testicular cord formation and neovascularization. The Vegfa gene has 8 exons with many splice variants. Vegfa120, Vegfa164, and Vegfa188 mRNA isoforms were detected on Embryonic Day (E) 13.5 (plug date = E0) in the rat. Vegfa120, Vegfa144, Vegfa164, Vegfa188, and Vegfa205 mRNA were detected at E18 and Postnatal Day 3 (P3). Kdr mRNA was present on E13.5, whereas Fms-like tyrosine kinase 1 receptor (Flt1) mRNA was not detected until E18. VEGFA protein was localized to Sertoli cells at cord formation and KDR to germ and interstitial cells. The VEGFA signaling inhibitors SU1498 (40 μM) and VEGFR-TKI (8 μM) inhibited cord formation in E13 testis cultures with 90{\%} reduced vascular density (P < 0.01) in VEGFR-TKI-treated organs. Furthermore, Je-11 (10 μM), an antagonist to VEGFA, also perturbed cord formation and inhibited vascular density by more than 50{\%} (P < 0.01). To determine signal transduction pathways involved in VEGFA's regulation of testis morphogenesis, E13 testis were treated with LY 294002 (15 μM), a phosphoinositide 3-kinase (P13K) pathway inhibitor, resulting in inhibition of both vascular density (46{\%}) and cord formation. Thus, we support our hypothesis and conclude that VEGFA, secreted by the Sertoli cell, is involved in both neovascularization and cord formation and potentially acts through the P13K pathway during testis morphogenesis to elicit its effects.",
keywords = "Growth factors, Sertoli cells, Testis",
author = "Bott, {Rebecca C.} and McFee, {Ryann M.} and Clopton, {Debra T.} and Candice Toombs and Cupp, {Andrea S.}",
year = "2006",
month = "7",
day = "1",
doi = "10.1095/biolreprod.105.047225",
language = "English (US)",
volume = "75",
pages = "56--67",
journal = "Biology of Reproduction",
issn = "0006-3363",
publisher = "Society for the Study of Reproduction",
number = "1",

}

TY - JOUR

T1 - Vascular endothelial growth factor and kinase domain region receptor are involved in both seminiferous cord formation and vascular development during testis morphogenesis in the rat

AU - Bott, Rebecca C.

AU - McFee, Ryann M.

AU - Clopton, Debra T.

AU - Toombs, Candice

AU - Cupp, Andrea S.

PY - 2006/7/1

Y1 - 2006/7/1

N2 - Morphological male sex determination is dependent on migration of endothelial and preperitubular cells from the adjacent mesonephros into the developing testis. Our hypothesis is that VEGFA and its receptor KDR are necessary for both testicular cord formation and neovascularization. The Vegfa gene has 8 exons with many splice variants. Vegfa120, Vegfa164, and Vegfa188 mRNA isoforms were detected on Embryonic Day (E) 13.5 (plug date = E0) in the rat. Vegfa120, Vegfa144, Vegfa164, Vegfa188, and Vegfa205 mRNA were detected at E18 and Postnatal Day 3 (P3). Kdr mRNA was present on E13.5, whereas Fms-like tyrosine kinase 1 receptor (Flt1) mRNA was not detected until E18. VEGFA protein was localized to Sertoli cells at cord formation and KDR to germ and interstitial cells. The VEGFA signaling inhibitors SU1498 (40 μM) and VEGFR-TKI (8 μM) inhibited cord formation in E13 testis cultures with 90% reduced vascular density (P < 0.01) in VEGFR-TKI-treated organs. Furthermore, Je-11 (10 μM), an antagonist to VEGFA, also perturbed cord formation and inhibited vascular density by more than 50% (P < 0.01). To determine signal transduction pathways involved in VEGFA's regulation of testis morphogenesis, E13 testis were treated with LY 294002 (15 μM), a phosphoinositide 3-kinase (P13K) pathway inhibitor, resulting in inhibition of both vascular density (46%) and cord formation. Thus, we support our hypothesis and conclude that VEGFA, secreted by the Sertoli cell, is involved in both neovascularization and cord formation and potentially acts through the P13K pathway during testis morphogenesis to elicit its effects.

AB - Morphological male sex determination is dependent on migration of endothelial and preperitubular cells from the adjacent mesonephros into the developing testis. Our hypothesis is that VEGFA and its receptor KDR are necessary for both testicular cord formation and neovascularization. The Vegfa gene has 8 exons with many splice variants. Vegfa120, Vegfa164, and Vegfa188 mRNA isoforms were detected on Embryonic Day (E) 13.5 (plug date = E0) in the rat. Vegfa120, Vegfa144, Vegfa164, Vegfa188, and Vegfa205 mRNA were detected at E18 and Postnatal Day 3 (P3). Kdr mRNA was present on E13.5, whereas Fms-like tyrosine kinase 1 receptor (Flt1) mRNA was not detected until E18. VEGFA protein was localized to Sertoli cells at cord formation and KDR to germ and interstitial cells. The VEGFA signaling inhibitors SU1498 (40 μM) and VEGFR-TKI (8 μM) inhibited cord formation in E13 testis cultures with 90% reduced vascular density (P < 0.01) in VEGFR-TKI-treated organs. Furthermore, Je-11 (10 μM), an antagonist to VEGFA, also perturbed cord formation and inhibited vascular density by more than 50% (P < 0.01). To determine signal transduction pathways involved in VEGFA's regulation of testis morphogenesis, E13 testis were treated with LY 294002 (15 μM), a phosphoinositide 3-kinase (P13K) pathway inhibitor, resulting in inhibition of both vascular density (46%) and cord formation. Thus, we support our hypothesis and conclude that VEGFA, secreted by the Sertoli cell, is involved in both neovascularization and cord formation and potentially acts through the P13K pathway during testis morphogenesis to elicit its effects.

KW - Growth factors

KW - Sertoli cells

KW - Testis

UR - http://www.scopus.com/inward/record.url?scp=33745439265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745439265&partnerID=8YFLogxK

U2 - 10.1095/biolreprod.105.047225

DO - 10.1095/biolreprod.105.047225

M3 - Article

C2 - 16672722

AN - SCOPUS:33745439265

VL - 75

SP - 56

EP - 67

JO - Biology of Reproduction

JF - Biology of Reproduction

SN - 0006-3363

IS - 1

ER -