{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T15:25:28Z","timestamp":1785252328254,"version":"3.55.0"},"reference-count":27,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T00:00:00Z","timestamp":1626739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts primarily on endothelial cells, but numerous studies suggest that VEGF also acts on non-endothelial cells, including trophoblast cells. Inhibition of VEGF signaling by excess production of the endogenous soluble VEGF receptor sFlt1 in trophoblast cells has been implicated in several pregnancy complications. Our previous studies and other reports have shown that VEGF directly regulates placental vascular development and functions and that excess VEGF production adversely affects placental vascular development. Trophoblast giant cells (TGCs) line the maternal side of the placental vasculature in mice and function like endothelial cells. In this study, we specifically examined the effect of excess VEGF signaling on TGC development associated with defective placental vascular development using two mouse models an endometrial VEGF overexpression model and a placenta-specific sFlt1 knockdown model. Placentas of endometrial VEGF-overexpressing dams at embryonic days (E) 11.5 and 14.5 showed dramatic enlargement of the venous maternal spaces in junctional zones. The size and number of the parietal TGCs that line these venous spaces in the placenta were also significantly increased. Although junctional zone venous blood spaces from control and VEGF-overexpressing dams were not markedly different in size at E17.5, the number and size of P-TGCs were both significantly increased in the placentas from VEGF-overexpressing dams. In sFlt1 knockdown placentas, however, there was a significant increase in the size of the sinusoidal TGC-lined, alkaline phosphatase-positive maternal blood spaces in the labyrinth. These results suggest that VEGF signaling plays an important role in maintaining the homeostasis of the maternal vascular space in the mouse placenta through modulation of TGC development and differentiation, similar to the effect of VEGF on endothelial cells in other vascular beds.<\/jats:p>","DOI":"10.3390\/biom11071062","type":"journal-article","created":{"date-parts":[[2021,7,20]],"date-time":"2021-07-20T11:26:10Z","timestamp":1626780370000},"page":"1062","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["VEGF Maintains Maternal Vascular Space Homeostasis in the Mouse Placenta through Modulation of Trophoblast Giant Cell Functions"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3322-1857","authenticated-orcid":false,"given":"Xiujun","family":"Fan","sequence":"first","affiliation":[{"name":"Laboratory of Reproductive Health, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9552-2175","authenticated-orcid":false,"given":"Shanmugam","family":"Muruganandan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Biology, Northeastern University, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philemon D","family":"Shallie","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabita","family":"Dhal","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Petitt","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihar R","family":"Nayak","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Obstetrics and Gynecology, UMKC School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/380439a0","article-title":"Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene","volume":"380","author":"Ferrara","year":"1996","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/380435a0","article-title":"Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele","volume":"380","author":"Carmeliet","year":"1996","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"151019","DOI":"10.1242\/dev.151019","article-title":"Vascular endothelial growth factor signaling in development and disease","volume":"145","author":"Karaman","year":"2018","journal-title":"Development"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1016\/S0002-9440(10)62567-9","article-title":"Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome","volume":"160","author":"Zhou","year":"2002","journal-title":"Am. J. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ydbio.2014.01.015","article-title":"Development of the hemochorial maternal vascular spaces in the placenta through endothelial and vasculogenic mimicry","volume":"387","author":"Rai","year":"2014","journal-title":"Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.ydbio.2007.01.009","article-title":"Diverse subtypes and developmental origins of trophoblast giant cells in the mouse placenta","volume":"304","author":"Simmons","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1387\/ijdb.082768dh","article-title":"Development and function of trophoblast giant cells in the rodent placenta","volume":"54","author":"Hu","year":"2010","journal-title":"Int. J. Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jena, M.K., Sharma, N.R., Petitt, M., Maulik, D., and Nayak, N.R. (2020). Pathogenesis of Preeclampsia and Therapeutic Approaches Targeting the Placenta. Biomolecules, 10.","DOI":"10.3390\/biom10060953"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4941","DOI":"10.1172\/JCI76864","article-title":"Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications","volume":"124","author":"Fan","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1210\/mend.13.4.0265","article-title":"Alternative splicing of vascular endothelial growth factor (VEGF)-R1 (FLT-1) pre-mRNA is important for the regulation of VEGF activity","volume":"13","author":"He","year":"1999","journal-title":"Mol. Endocrinol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"123717","DOI":"10.1155\/2011\/123717","article-title":"Disrupted balance of angiogenic and antiangiogenic signalings in preeclampsia","volume":"2011","author":"Furuya","year":"2011","journal-title":"J. Pregnancy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/j.mam.2012.12.008","article-title":"Placental trophoblast cell differentiation: Physiological regulation and pathological relevance to preeclampsia","volume":"34","author":"Ji","year":"2013","journal-title":"Mol. Aspects Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrm1911","article-title":"VEGF receptor signalling\u2014In control of vascular function","volume":"7","author":"Olsson","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1006\/dbio.2000.9744","article-title":"VEGF regulates cell behavior during vasculogenesis","volume":"224","author":"Drake","year":"2000","journal-title":"Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.humimm.2021.02.013","article-title":"Contribution of macrophages to fetomaternal immunological tolerance","volume":"82","author":"Parasar","year":"2021","journal-title":"Hum. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1093\/biolreprod\/85.s1.478","article-title":"A Novel Method of Local Gene Delivery and Noninvasive Imaging of Transgene Expression in the Mouse Endometrium","volume":"85","author":"Fan","year":"2011","journal-title":"Biol. Reprod."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5637","DOI":"10.1210\/en.2012-1556","article-title":"Transient, inducible, placenta-specific gene expression in mice","volume":"153","author":"Fan","year":"2012","journal-title":"Endocrinology"},{"key":"ref_19","first-page":"275","article-title":"Phenotypic analysis of the mouse placenta","volume":"121","author":"Natale","year":"2006","journal-title":"Methods Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1126\/science.282.5396.2072","article-title":"Promotion of trophoblast stem cell proliferation by FGF4","volume":"282","author":"Tanaka","year":"1998","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0076-6879(06)19015-1","article-title":"Trophoblast stem cells","volume":"419","author":"Oda","year":"2006","journal-title":"Methods Enzymol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ydbio.2014.11.023","article-title":"Three-dimensional cultures of trophoblast stem cells autonomously develop vascular-like spaces lined by trophoblast giant cells","volume":"398","author":"Rai","year":"2015","journal-title":"Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrm3176","article-title":"Molecular control of endothelial cell behaviour during blood vessel morphogenesis","volume":"12","author":"Herbert","year":"2011","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.1101\/gad.199828.112","article-title":"Blimp1\/Prdm1 governs terminal differentiation of endovascular trophoblast giant cells and defines multipotent progenitors in the developing placenta","volume":"26","author":"Mould","year":"2012","journal-title":"Genes Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s10456-006-9055-8","article-title":"Vascular endothelial growth factor receptor-1 (VEGFR-1\/Flt-1): A dual regulator for angiogenesis","volume":"9","author":"Shibuya","year":"2006","journal-title":"Angiogenesis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00005-019-00552-7","article-title":"Role of Macrophages in Pregnancy and Related Complications","volume":"67","author":"Jena","year":"2019","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15637","DOI":"10.1073\/pnas.2635424100","article-title":"Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal\u2013fetal interface in the mouse placenta","volume":"100","author":"Hirashima","year":"2003","journal-title":"Proc. Natl. Acad. Sci. 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