{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:43:21Z","timestamp":1793727801262,"version":"4.6.1"},"reference-count":52,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Research Council of New Zealand","award":["HRC 21\/209"],"award-info":[{"award-number":["HRC 21\/209"]}]},{"name":"China Scholarship Council (CSC) scholarships","award":["HRC 21\/209"],"award-info":[{"award-number":["HRC 21\/209"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Placental extracellular vesicles (EVs) have increasingly been recognized as a major mediator of feto-maternal communication. However, the cellular and molecular mechanisms of the uptake of placental EVs by recipient cells are still not well-understood. We previously reported that placental EVs target a limited number of organs in vivo. In the current study, we investigated the mechanisms underlying the uptake of placental EVs into target cells. Placental EVs were derived from explant cultures of normal or preeclamptic placentae. The mechanisms underlying the uptake of placental EVs were elucidated, using the phagocytosis or endocytosis inhibitor, trypsin-treatment or integrin-blocking peptides. The endothelial cell activation was studied using the monocyte adhesion assay after the preeclamptic EVs exposure, with and\/or without treatment with the integrin blocking peptide, YIGSR. The cellular mechanism of the uptake of the placental EVs was time, concentration and energy-dependent and both the phagocytosis and endocytosis were involved in this process. Additionally, proteins on the surface of the placental EVs, including integrins, were involved in the EV uptake process. Furthermore, inhibiting the uptake of preeclamptic EVs with YIGSR, reduced the endothelial cell activation. The interaction between the placental EVs and the recipient cells is mediated by integrins, and the cellular uptake is mediated by a combination of both phagocytosis and endocytosis.<\/jats:p>","DOI":"10.3390\/ijms232113115","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T04:57:34Z","timestamp":1667105854000},"page":"13115","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The Blocking of Integrin-Mediated Interactions with Maternal Endothelial Cells Reversed the Endothelial Cell Dysfunction Induced by EVs, Derived from Preeclamptic Placentae"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-0930","authenticated-orcid":false,"given":"Yourong","family":"Feng","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5894-6331","authenticated-orcid":false,"given":"Qi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7543-5138","authenticated-orcid":false,"given":"Sien Yee","family":"Lau","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5964-4968","authenticated-orcid":false,"given":"Bridget W.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie","family":"Groom","sequence":"additional","affiliation":[{"name":"Liggins Institute, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn J.","family":"Barrett","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7501-1340","authenticated-orcid":false,"given":"Lawrence W.","family":"Chamley","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand"},{"name":"Hub for Extracellular Vesicles Investigations (HEVI), University of Auckland, Auckland 1023, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/1479-5876-12-204","article-title":"Placenta-derived exosomes continuously increase in maternal circulation over the first trimester of pregnancy","volume":"12","author":"Sarker","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1535750","DOI":"10.1080\/20013078.2018.1535750","article-title":"Minimal information for studies of extracellular vesicles 2018 (MISEV2018): A position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines","volume":"7","author":"Witwer","year":"2018","journal-title":"J. Extracell. Vesicles"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1161\/HYPERTENSIONAHA.119.14081","article-title":"Unique microRNA Signals in Plasma Exosomes from Pregnancies Complicated by Preeclampsia","volume":"75","author":"Li","year":"2020","journal-title":"Hypertension"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1093\/humrep\/dew004","article-title":"Proteomic characterization of macro-, micro- and nano-extracellular vesicles derived from the same first trimester placenta: Relevance for feto-maternal communication","volume":"31","author":"Tong","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Tang, Y., Sun, X., Kang, M., Zhao, M., Wan, J., and Chen, Q. (2022). Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss. Cells, 11.","DOI":"10.3390\/cells11182772"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e13297","DOI":"10.1111\/aji.13297","article-title":"Placental extracellular vesicles and pre-eclampsia","volume":"85","author":"Schuster","year":"2021","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.placenta.2020.03.002","article-title":"Placental small extracellular vesicles: Current questions and investigative opportunities","volume":"102","author":"Sadovsky","year":"2020","journal-title":"Placenta"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1097\/IGC.0000000000001140","article-title":"Phagocytosis of Extracellular Vesicles Extruded From the Placenta by Ovarian Cancer Cells Inhibits Growth of the Cancer Cells","volume":"28","author":"Chen","year":"2018","journal-title":"Int. J. Gynecol. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.placenta.2020.07.006","article-title":"Placental syncytiotrophoblast extracellular vesicles enter primary endothelial cells through clathrin-mediated endocytosis","volume":"100","author":"Cronqvist","year":"2020","journal-title":"Placenta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1812261","DOI":"10.1080\/20013078.2020.1812261","article-title":"Internalization of trophoblastic small extracellular vesicles and detection of their miRNA cargo in P-bodies","volume":"9","author":"Li","year":"2020","journal-title":"J. Extracell. Vesicles"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1530\/REP-16-0615","article-title":"In vivo targets of human placental micro-vesicles vary with exposure time and pregnancy","volume":"153","author":"Tong","year":"2017","journal-title":"Reproduction"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1182\/blood-2011-02-338004","article-title":"Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes","volume":"119","author":"Montecalvo","year":"2012","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"24641","DOI":"10.3402\/jev.v3.24641","article-title":"Routes and mechanisms of extracellular vesicle uptake","volume":"3","author":"Mulcahy","year":"2014","journal-title":"J. Extracell. Vesicles"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14","DOI":"10.15212\/ZOONOSES-2022-0004","article-title":"Current understanding of extracellular vesicle homing\/tropism","volume":"2","author":"Edelmann","year":"2022","journal-title":"Zoonoses"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.semcdb.2017.01.002","article-title":"Extracellular vesicle docking at the cellular port: Extracellular vesicle binding and uptake","volume":"67","author":"French","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.1038\/s41598-021-82752-w","article-title":"Integrins mediate placental extracellular vesicle trafficking to lung and liver in vivo","volume":"11","author":"Nguyen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1007\/s13273-019-0026-8","article-title":"Roles of integrins in regulating metastatic potentials of cancer cell derived exosomes","volume":"15","author":"Soung","year":"2019","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1093\/humrep\/dex310","article-title":"Placental Nano-vesicles Target to Specific Organs and Modulate Vascular Tone In Vivo","volume":"32","author":"Tong","year":"2017","journal-title":"Hum. Reprod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.placenta.2022.01.008","article-title":"Antiphospholipid antibodies do not cause retargeting of placental extracellular vesicles in the maternal body","volume":"118","author":"Tsai","year":"2022","journal-title":"Placenta"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"619829","DOI":"10.1155\/2014\/619829","article-title":"Characterization of uptake and internalization of exosomes by bladder cancer cells","volume":"2014","author":"Franzen","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12964-020-00630-w","article-title":"Inhibition of \u03b1v\u03b23 integrin impairs adhesion and uptake of tumor-derived small extracellular vesicles","volume":"18","author":"Altei","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15847","DOI":"10.1038\/s41598-019-52127-3","article-title":"Extracellular vesicle integrins act as a nexus for platelet adhesion in cerebral microvessels","volume":"9","author":"Bagi","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1089\/scd.2011.0615","article-title":"Tailored integrin-extracellular matrix interactions to direct human mesenchymal stem cell differentiation","volume":"21","author":"Frith","year":"2012","journal-title":"Stem Cells Dev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1146\/annurev.cellbio.12.1.697","article-title":"RGD and other recognition sequences for integrins","volume":"12","author":"Ruoslahti","year":"1996","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fendo.2017.00174","article-title":"Micro- and Nano-vesicles from First Trimester Human Placentae Carry Flt-1 and Levels Are Increased in Severe Preeclampsia","volume":"8","author":"Tong","year":"2017","journal-title":"Front. Endocrinol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.placenta.2014.07.009","article-title":"Trophoblast debris extruded from preeclamptic placentae activates endothelial cells: A mechanism by which the placenta communicates with the maternal endothelium","volume":"35","author":"Shen","year":"2014","journal-title":"Placenta"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Salomon, C., Torres, M.J., Kobayashi, M., Scholz-Romero, K., Sobrevia, L., Dobierzewska, A., Illanes, S.E., Mitchell, M.D., and Rice, G.E. (2014). A Gestational Profile of Placental Exosomes in Maternal Plasma and Their Effects on Endothelial Cell Migration. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098667"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.placenta.2018.10.009","article-title":"Estimation of the burden of human placental micro- and nano-vesicles extruded into the maternal blood from 8 to 12 weeks of gestation","volume":"72\u201373","author":"Liu","year":"2018","journal-title":"Placenta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.placenta.2012.03.007","article-title":"Phagocytosis of apoptotic trophoblastic debris protects endothelial cells against activation","volume":"33","author":"Chen","year":"2012","journal-title":"Placenta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e12085","DOI":"10.1002\/jev2.12085","article-title":"Biodistribution of extracellular vesicles following administration into animals: A systematic review","volume":"10","author":"Kang","year":"2021","journal-title":"J. Extracell. Vesicles"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.nano.2016.12.009","article-title":"Size-dependent cellular uptake of exosomes","volume":"13","author":"Caponnetto","year":"2017","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5391","DOI":"10.1021\/nl2030213","article-title":"Receptor-Mediated Endocytosis of Nanoparticles of Various Shapes","volume":"11","author":"Frenkel","year":"2011","journal-title":"Nano Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.biomaterials.2016.09.029","article-title":"Exosomes as biomimetic tools for stem cell differentiation: Applications in dental pulp tissue regeneration","volume":"111","author":"Huang","year":"2016","journal-title":"Biomaterials"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1038\/s41598-017-04468-0","article-title":"Syncytiotrophoblast derived extracellular vesicles transfer functional placental miRNAs to primary human endothelial cells","volume":"7","author":"Cronqvist","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/nature15756","article-title":"Tumour exosome integrins determine organotropic metastasis","volume":"527","author":"Hoshino","year":"2015","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2810","DOI":"10.1111\/j.1538-7836.2010.04088.x","article-title":"Internalization of microparticles by endothelial cells promotes platelet\/endothelial cell interaction under flow","volume":"8","author":"Terrisse","year":"2010","journal-title":"J. Thromb. Haemost."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1002\/stem.1161","article-title":"Human Liver Stem Cell-Derived Microvesicles Inhibit Hepatoma Growth in SCID Mice by Delivering Antitumor MicroRNAs","volume":"30","author":"Fonsato","year":"2012","journal-title":"Stem Cells"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/ncb3090","article-title":"Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth","volume":"17","author":"Zhou","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1706801","DOI":"10.1080\/20013078.2019.1706801","article-title":"Activated human astrocyte-derived extracellular vesicles modulate neuronal uptake, differentiation and firing","volume":"9","author":"You","year":"2020","journal-title":"J. Extracell. Vesicles"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1126\/science.2961059","article-title":"YIGSR, a synthetic laminin pentapeptide, inhibits experimental metastasis formation","volume":"238","author":"Iwamoto","year":"1987","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4852","DOI":"10.1073\/pnas.1017667108","article-title":"Cancer cell-derived microvesicles induce transformation by transferring tissue transglutaminase and fibronectin to recipient cells","volume":"108","author":"Antonyak","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Middleton, J.D., Sivakumar, S., and Hai, T. (2021). Chemotherapy-Induced Changes in the Lung Microenvironment: The Role of MMP-2 in Facilitating Intravascular Arrest of Breast Cancer Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910280"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ludwig, B.S., Kessler, H., Kossatz, S., and Reuning, U. (2021). RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. Cancers, 13.","DOI":"10.3390\/cancers13071711"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1159\/000430283","article-title":"Differential Proteomic Analysis of Syncytiotrophoblast Extracellular Vesicles from Early-Onset Severe Preeclampsia, using 8-Plex iTRAQ Labeling Coupled with 2D Nano LC-MS\/MS","volume":"36","author":"Li","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1161\/HYPERTENSIONAHA.117.09321","article-title":"Placental Vesicles Carry Active Endothelial Nitric Oxide Synthase and Their Activity is Reduced in Preeclampsia","volume":"70","author":"Kandzija","year":"2017","journal-title":"Hypertension"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jri.2016.08.008","article-title":"Update of syncytiotrophoblast derived extracellular vesicles in normal pregnancy and preeclampsia","volume":"119","author":"Tannetta","year":"2017","journal-title":"J. Reprod. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.preghy.2014.02.001","article-title":"The classification, diagnosis and management of the hypertensive disorders of pregnancy: A revised statement from the ISSHP","volume":"4","author":"Tranquilli","year":"2014","journal-title":"Pregnancy Hypertens."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1093\/molehr\/gal073","article-title":"An in vitro model of human placental trophoblast deportation\/shedding","volume":"12","author":"Abumaree","year":"2006","journal-title":"Mol. Hum. Reprod."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.12688\/f1000research.27393.1","article-title":"Towards establishing extracellular vesicle-associated RNAs as biomarkers for HER2+ breast cancer","volume":"9","author":"Hisey","year":"2020","journal-title":"F1000Research"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Horibe, S., Tanahashi, T., Kawauchi, S., Murakami, Y., and Rikitake, Y. (2018). Mechanism of recipient cell-dependent differences in exosome uptake. BMC Cancer, 18.","DOI":"10.1186\/s12885-017-3958-1"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1016\/j.jconrel.2015.09.031","article-title":"Microvesicle- and exosome-mediated drug delivery enhances the cytotoxicity of Paclitaxel in autologous prostate cancer cells","volume":"220","author":"Saari","year":"2015","journal-title":"J. Control. Release"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1093\/cvr\/cvs279","article-title":"Calcium channel blockers prevent endothelial cell activation in response to necrotic trophoblast debris: Possible relevance to pre-eclampsia","volume":"96","author":"Chen","year":"2012","journal-title":"Cardiovasc. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13115\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:05:03Z","timestamp":1760144703000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/21\/13115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":52,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["ijms232113115"],"URL":"https:\/\/doi.org\/10.3390\/ijms232113115","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]}}}