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Divergent vascular endothelial growth factor A (VEGFA) signaling determines spermatogonial stem cell fate
Vascular endothelial growth factor A (VEGFA) has been implicated in male fertility, namely in maintenance of spermatogonial stem cells (SSC). The Vegfa gene can be spliced into divergent isoform family types- angiogenic and antiangiogenic. VEGFA can bind to neuropilin-1 (NRP1), a co-receptor that enhances the signal transduction of angiogenic VEGFA isoforms but not the antiangiogenic isoforms since they lack a NRP1 binding site. We hypothesized that angiogenic VEGFA and NRP1 maintain a healthy SSC pool while the antiangiogenic VEGFA isoforms reduce the number of viable SSCs- either by differentiating them or by inducing apoptosis. The current studies aim to better understand how VEGFA isoforms regulate SSC maintenance, how NRP1 regulates the balance of VEGFA pro- to antiangiogenic isoform activity for SSCs, and what cell types may be the most critical source of VEGFA and/or NRP1 for ensuring male fertility. Elimination of both VEGFA isoform types in Sertoli and germ cells of mouse testes reduced male fertility and reduced sperm counts despite compensatory increases in genes known to promote SSC maintenance (Ret, Sin3a, and Neurog3). Elimination of NRP1 from Sertoli and Leydig cells reduced angiogenic VEGFA signaling. Fertility was reduced, and the genes that were upregulated in the previous study were downregulated (Gdnf, Ret, Sin3a, Neurog3, Foxo1, and Kitl). Additionally, NRP1 loss reduced phosphorylation of RET, the GDNF receptor and a major initiator of SSC self-renewal. Elimination of NRP1 also appeared to accelerate germ cell loss, possibly due to apoptosis. To compare the effect on SSC maintenance by loss of all VEGFA isoforms to inhibiting just angiogenic isoform signaling, we used Sertoli cell-specific knockouts of both NRP1 and VEGFA. Males had reduced fertility in both cases, and preliminary findings suggest transplantation with cells using them as donors results in reduced SSC colonization. Finally, a study in rats utilized treatment with an antibody to VEGFA antiangiogenic isoforms that reduced the number of ID4-positive spermatogonia as well as how many were located at the basement membrane of seminiferous tubules. Taken together, these findings further implicate the importance of regulating VEGFA signaling to ensure SSC maintenance and male fertility.
Sargent, Kevin M, "Divergent vascular endothelial growth factor A (VEGFA) signaling determines spermatogonial stem cell fate" (2016). ETD collection for University of Nebraska - Lincoln. AAI10247735.