Loss of Vascular Endothelial Growth Factor A (VEGFA) isoforms in the testes of male mice causes subfertility, reduces sperm numbers, and alters expression of genes that regulate undifferentiated spermatogonia

Ningxia Lu, Kevin M. Sargent, Debra T. Clopton, William E. Pohlmeier, Vanessa M. Brauer, Renee M. McFee, John S. Weber, Napoleone Ferrara, David W. Silversides, Andrea S. Cupp

Research output: Contribution to journalArticle

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Abstract

Vascular endothelial growth factor A (VEGFA) isoform treatment has been demonstrated to alter spermatogonial stem cell homeostasis. Therefore, we generated pDmrt1-Cre;Vegfa-/- (knockout, KO) mice by crossing pDmrt1-Cre mice to floxed Vegfa mice to test whether loss of all VEGFA isoforms in Sertoli and germ cells would impair spermatogenesis. When first mated, KOmales took 14 days longer to get control females pregnant (P < .02) and tended to take longer for all subsequent parturition intervals (9 days; P < .07). Heterozygous males sired fewer pups per litter (P < .03) and after the first litter took 10 days longer (P < .05) to impregnate females, suggesting a more progressive loss of fertility. Reproductive organs were collected from 6-month-old male mice. There were fewer sperm per tubule in the corpus epididymides (P < .001)andfewer ZBTB16-stained undifferentiated spermatogonia (P < .003) in the testes of KO males. Testicular mRNA abundance for Bcl2 (P < .02), Bcl2:Bax (P < .02), Neurog3 (P < .007), and Ret was greater (P = .0005), tended to be greater for Sin3a and tended to be reduced for total Foxo1 (P < .07) in KO males. Immunofluorescence for CD31 and VE-Cadherin showed no differences in testis vasculature; however, CD31-positive staining was evident in undifferentiated spermatogonia only in KO testes. Therefore, loss of VEGFA isoforms in Sertoli and germ cells alters genes necessary for long-term maintenance of undifferentiated spermatogonia, ultimately reducing sperm numbers and resulting in subfertility.

Original languageEnglish (US)
Pages (from-to)4790-4802
Number of pages13
JournalEndocrinology
Volume154
Issue number12
DOIs
StatePublished - Dec 1 2013

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Spermatogonia
Sperm Count
Infertility
Vascular Endothelial Growth Factor A
Testis
Protein Isoforms
Gene Expression
Sertoli Cells
Germ Cells
Epididymis
Spermatogenesis
Knockout Mice
Fluorescent Antibody Technique
Fertility
Spermatozoa
Homeostasis
Stem Cells
Parturition
Staining and Labeling
Messenger RNA

ASJC Scopus subject areas

  • Endocrinology

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Loss of Vascular Endothelial Growth Factor A (VEGFA) isoforms in the testes of male mice causes subfertility, reduces sperm numbers, and alters expression of genes that regulate undifferentiated spermatogonia. / Lu, Ningxia; Sargent, Kevin M.; Clopton, Debra T.; Pohlmeier, William E.; Brauer, Vanessa M.; McFee, Renee M.; Weber, John S.; Ferrara, Napoleone; Silversides, David W.; Cupp, Andrea S.

In: Endocrinology, Vol. 154, No. 12, 01.12.2013, p. 4790-4802.

Research output: Contribution to journalArticle

Lu, Ningxia ; Sargent, Kevin M. ; Clopton, Debra T. ; Pohlmeier, William E. ; Brauer, Vanessa M. ; McFee, Renee M. ; Weber, John S. ; Ferrara, Napoleone ; Silversides, David W. ; Cupp, Andrea S. / Loss of Vascular Endothelial Growth Factor A (VEGFA) isoforms in the testes of male mice causes subfertility, reduces sperm numbers, and alters expression of genes that regulate undifferentiated spermatogonia. In: Endocrinology. 2013 ; Vol. 154, No. 12. pp. 4790-4802.
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abstract = "Vascular endothelial growth factor A (VEGFA) isoform treatment has been demonstrated to alter spermatogonial stem cell homeostasis. Therefore, we generated pDmrt1-Cre;Vegfa-/- (knockout, KO) mice by crossing pDmrt1-Cre mice to floxed Vegfa mice to test whether loss of all VEGFA isoforms in Sertoli and germ cells would impair spermatogenesis. When first mated, KOmales took 14 days longer to get control females pregnant (P < .02) and tended to take longer for all subsequent parturition intervals (9 days; P < .07). Heterozygous males sired fewer pups per litter (P < .03) and after the first litter took 10 days longer (P < .05) to impregnate females, suggesting a more progressive loss of fertility. Reproductive organs were collected from 6-month-old male mice. There were fewer sperm per tubule in the corpus epididymides (P < .001)andfewer ZBTB16-stained undifferentiated spermatogonia (P < .003) in the testes of KO males. Testicular mRNA abundance for Bcl2 (P < .02), Bcl2:Bax (P < .02), Neurog3 (P < .007), and Ret was greater (P = .0005), tended to be greater for Sin3a and tended to be reduced for total Foxo1 (P < .07) in KO males. Immunofluorescence for CD31 and VE-Cadherin showed no differences in testis vasculature; however, CD31-positive staining was evident in undifferentiated spermatogonia only in KO testes. Therefore, loss of VEGFA isoforms in Sertoli and germ cells alters genes necessary for long-term maintenance of undifferentiated spermatogonia, ultimately reducing sperm numbers and resulting in subfertility.",
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AU - Brauer, Vanessa M.

AU - McFee, Renee M.

AU - Weber, John S.

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AU - Silversides, David W.

AU - Cupp, Andrea S.

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