title: Vascular endothelial growth factor A: just one of multiple mechanisms for sex-specific vascular development within the testis?
abstract: 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. Many in vitro experiments 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 vivo models 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(-/-) and Sry-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. A Vegfa signal transduction array was employed on postnatal testes from Sry-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.
authors.affiliation: Department of Animal ScienceUniversity of Nebraska-Lincoln, Animal Science Building, 3940 Fair Street, Lincoln, Nebraska 68583-0908, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Sargent
authors.affiliation: Department of Animal ScienceUniversity of Nebraska-Lincoln, Animal Science Building, 3940 Fair Street, Lincoln, Nebraska 68583-0908, USA.
authors.forename: Renee M
authors.initials: RM
authors.lastname: McFee
authors.affiliation: Department of Animal ScienceUniversity of Nebraska-Lincoln, Animal Science Building, 3940 Fair Street, Lincoln, Nebraska 68583-0908, USA.
authors.forename: Renata
authors.initials: R
authors.lastname: Spuri Gomes
authors.affiliation: Department of Animal ScienceUniversity of Nebraska-Lincoln, Animal Science Building, 3940 Fair Street, Lincoln, Nebraska 68583-0908, USA acupp2@unl.edu.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Cupp
mesh_terms: D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic / Q000235:genetics*; D012727:Sex Characteristics; D012733:Sex Differentiation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013737:Testis / Q000098:blood supply* / Q000196:embryology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: VEGFA; sex differentiation; testis; vasculature