{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T14:39:28Z","timestamp":1768315168413,"version":"3.49.0"},"reference-count":86,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T00:00:00Z","timestamp":1618790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education","award":["NRF-2016R1D1A1B03933337, NRF-2019R1I1A1A01059738, and NRF-2017R1D1A1B03029081"],"award-info":[{"award-number":["NRF-2016R1D1A1B03933337, NRF-2019R1I1A1A01059738, and NRF-2017R1D1A1B03029081"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The abnormal development or disruption of the lymphatic vasculature has been implicated in metabolic and hypertensive diseases. Recent evidence suggests that the offspring exposed to preeclampsia (PE) in utero are at higher risk of long-term health problems, such as cardiovascular and metabolic diseases in adulthood, owing to in utero fetal programming. We aimed to investigate lymphangiogenic activities in the lymphatic endothelial progenitor cells (LEPCs) of the offspring of PE. Human umbilical cord blood LEPCs from pregnant women with severe PE (n = 10) and gestationally matched normal pregnancies (n = 10) were purified with anti-vascular endothelial growth factor receptor 3 (VEGFR3)\/podoplanin\/CD11b microbeads using a magnetic cell sorter device. LEPCs from PE displayed significantly delayed differentiation and reduced formation of lymphatic endothelial cell (LEC) colonies compared with the LEPCs from normal pregnancies. LECs differentiated from PE-derived LEPCs exhibited decreased tube formation, migration, proliferation, adhesion, wound healing, and 3D-sprouting activities as well as increased lymphatic permeability through the disorganization of VE-cadherin junctions, compared with the normal pregnancy-derived LECs. In vivo, LEPCs from PE showed significantly reduced lymphatic vessel formation compared to the LEPCs of the normal pregnancy. Gene expression analysis revealed that compared to the normal pregnancy-derived LECs, the PE-derived LECs showed a significant decrease in the expression of pro-lymphangiogenic genes (GREM1, EPHB3, VEGFA, AMOT, THSD7A, ANGPTL4, SEMA5A, FGF2, and GBX2). Collectively, our findings demonstrate, for the first time, that LEPCs from PE have reduced lymphangiogenic activities in vitro and in vivo and show the decreased expression of pro-lymphangiogenic genes. This study opens a new avenue for investigation of the molecular mechanism of LEPC differentiation and lymphangiogenesis in the offspring of PE and subsequently may impact the treatment of long-term health problems such as cardiovascular and metabolic disorders of offspring with abnormal development of lymphatic vasculature.<\/jats:p>","DOI":"10.3390\/ijms22084237","type":"journal-article","created":{"date-parts":[[2021,4,19]],"date-time":"2021-04-19T11:21:38Z","timestamp":1618831298000},"page":"4237","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Decreased Lymphangiogenic Activities and Genes Expression of Cord Blood Lymphatic Endothelial Progenitor Cells (VEGFR3+\/Pod+\/CD11b+ Cells) in Patient with Preeclampsia"],"prefix":"10.3390","volume":"22","author":[{"given":"Hayan","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University Health System, Seoul 03722, Korea"},{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3009-6325","authenticated-orcid":false,"given":"Ja-Young","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University Health System, Seoul 03722, Korea"},{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeeun","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Korea"},{"name":"Program in Biochemistry, Cellular &amp; Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1694-8405","authenticated-orcid":false,"given":"Yong-Sun","family":"Maeng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Institute of Women\u2019s Life Medical Science, Yonsei University Health System, Seoul 03722, Korea"},{"name":"Department of Obstetrics and Gynecology, Yonsei University College of Medicine, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.tem.2014.11.005","article-title":"Peri-conception parental obesity, reproductive health, and transgenerational impacts","volume":"26","author":"Lane","year":"2015","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra0708473","article-title":"Effect of in utero and early-life conditions on adult health and disease","volume":"359","author":"Gluckman","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.preghy.2018.02.003","article-title":"Maternal pre-eclampsia and long-term offspring health: Is there a shadow cast?","volume":"12","author":"Goffin","year":"2018","journal-title":"Pregnancy Hypertens."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"953150","DOI":"10.1155\/2013\/953150","article-title":"Preeclampsia is a biomarker for vascular disease in both mother and child: The need for a medical alert system","volume":"2013","author":"Hakim","year":"2013","journal-title":"Int. J. Pediatr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1042\/CS20110627","article-title":"Pre-eclampsia and offspring cardiovascular health: Mechanistic insights from experimental studies","volume":"123","author":"Davis","year":"2012","journal-title":"Clin. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1552","DOI":"10.1542\/peds.2011-3093","article-title":"Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: A systematic review","volume":"129","author":"Davis","year":"2012","journal-title":"Pediatrics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1097\/AOG.0b013e3181f3a1f9","article-title":"Maternal pregnancy-related hypertension and risk for hypertension in offspring later in life","volume":"116","author":"Palmsten","year":"2010","journal-title":"Obstet Gynecol"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1161\/STROKEAHA.108.538025","article-title":"Pre-eclampsia is associated with increased risk of stroke in the adult offspring: The Helsinki birth cohort study","volume":"40","author":"Kajantie","year":"2009","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"918","DOI":"10.2337\/dc06-1881","article-title":"Prenatal exposures and glucose metabolism in adulthood: Are effects mediated through birth weight and adiposity?","volume":"30","author":"Thomas","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s00125-006-0558-z","article-title":"Pre-eclampsia and the later development of type 2 diabetes in mothers and their children: An intergenerational study from the Walker cohort","volume":"50","author":"Libby","year":"2007","journal-title":"Diabetologia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1136\/adc.2008.150870","article-title":"Pubertal anthropometry in sons and daughters of women with preeclamptic or normotensive pregnancies","volume":"94","author":"Ogland","year":"2009","journal-title":"Arch. Dis. Child."},{"key":"ref_12","first-page":"529","article-title":"Intrauterine exposure to preeclampsia and adolescent blood pressure, body size, and age at menarche in female offspring","volume":"101","author":"Vatten","year":"2003","journal-title":"Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1136\/jech-2015-205483","article-title":"Hypertensive disorders of pregnancy and adult offspring cardiometabolic outcomes: A systematic review of the literature and meta-analysis","volume":"70","author":"Thoulass","year":"2016","journal-title":"J. Epidemiol. Community Health"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"269.e1","DOI":"10.1016\/j.ajog.2009.06.060","article-title":"Health of children born to mothers who had preeclampsia: A population-based cohort study","volume":"201","author":"Wu","year":"2009","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/ije\/dyu260","article-title":"Maternal complications in pregnancy and wheezing in early childhood: A pooled analysis of 14 birth cohorts","volume":"44","author":"Zugna","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1164\/rccm.200512-1978OC","article-title":"Maternal complications and procedures in pregnancy and at birth and wheezing phenotypes in children","volume":"175","author":"Rusconi","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jri.2016.05.002","article-title":"The impact of early- and late-onset preeclampsia on umbilical cord blood cell populations","volume":"116","author":"Herzog","year":"2016","journal-title":"J. Reprod. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5329","DOI":"10.1210\/jc.2005-0532","article-title":"Decrease and senescence of endothelial progenitor cells in patients with preeclampsia","volume":"90","author":"Sugawara","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1447-0756.2007.00555.x","article-title":"Decrease and dysfunction of endothelial progenitor cells in umbilical cord blood with maternal pre-eclampsia","volume":"33","author":"Xia","year":"2007","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e12970","DOI":"10.1111\/aji.12970","article-title":"Abnormal lymphatic vessel development is associated with decreased decidual regulatory T cells in severe preeclampsia","volume":"80","author":"Jung","year":"2018","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000100081","article-title":"Decreased endothelial progenitor cells in umbilical cord blood in severe preeclampsia","volume":"64","author":"Kwon","year":"2007","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s12079-012-0165-3","article-title":"Molecular mechanisms underlying the fetal programming of adult disease","volume":"6","author":"Vo","year":"2012","journal-title":"J. Cell. Commun. Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.placenta.2012.10.003","article-title":"The ever growing complexity of placental epigenetics\u2014Role in adverse pregnancy outcomes and fetal programming","volume":"33","author":"Novakovic","year":"2012","journal-title":"Placenta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13148-015-0052-x","article-title":"Genome-scale hypomethylation in the cord blood DNAs associated with early onset preeclampsia","volume":"7","author":"Ching","year":"2015","journal-title":"Clin. Epigenetics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.2337\/db14-1709","article-title":"Epigenetic regulation of placenta-specific 8 contributes to altered function of endothelial colony-forming cells exposed to intrauterine gestational diabetes mellitus","volume":"64","author":"Blue","year":"2015","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nri1258","article-title":"Lymphatic vasculature development","volume":"4","author":"Oliver","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1089\/lrb.2008.1008","article-title":"The lymphatic system in health and disease","volume":"6","author":"Cueni","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev-immunol-041015-055354","article-title":"The lymphatic system: Integral roles in immunity","volume":"35","author":"Randolph","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1093\/humupd\/dmp004","article-title":"Regulatory T-cells and immune tolerance in pregnancy: A new target for infertility treatment?","volume":"15","author":"Guerin","year":"2009","journal-title":"Hum. Reprod. Update"},{"key":"ref_30","first-page":"684","article-title":"Shaping of oeripheral T cell responses by lymphatic endothelial cells","volume":"7","author":"Humbert","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3054","DOI":"10.1002\/eji.201040523","article-title":"Dendritic cells adhere to and transmigrate across lymphatic endothelium in response to IFN-alpha","volume":"40","author":"Rouzaut","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1111\/j.1549-8719.2011.00113.x","article-title":"Lymphatics: At the interface of immunity, tolerance, and tumor metastasis","volume":"18","author":"Shields","year":"2011","journal-title":"Microcirculation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1053\/j.gastro.2017.01.022","article-title":"Defective lymphatics in Crohn\u2019s Disease: Tertiary lymphoid follicles plug the gap","volume":"152","author":"McNamee","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Yin, N., Zhang, N., Lal, G., Xu, J., Yan, M., Ding, Y., and Bromberg, J.S. (2011). Lymphangiogenesis is required for pancreatic islet inflammation and diabetes. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028023"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"884","DOI":"10.1177\/1535370217697385","article-title":"Lymphangiogenesis: Fuel, smoke, or extinguisher of inflammation\u2019s fire?","volume":"242","author":"Abouelkheir","year":"2017","journal-title":"Exp. Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1172\/JCI71611","article-title":"Lymphatic vessels and tertiary lymphoid organs","volume":"124","author":"Ruddle","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.cmet.2017.07.020","article-title":"The lymphatic vasculature: Its role in adipose metabolism and obesity","volume":"26","author":"Escobedo","year":"2017","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.2337\/db12-0844","article-title":"Enhanced lymph vessel density, remodeling, and inflammation are reflected by gene expression signatures in dermal lymphatic endothelial cells in type 2 diabetes","volume":"62","author":"Haemmerle","year":"2013","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s10456-013-9370-9","article-title":"GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2","volume":"16","author":"Coma","year":"2013","journal-title":"Angiogenesis"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.5604\/17322693.1177170","article-title":"Angiogenesis and lymphangiogenesis in primary cutaneous T-cell lymphomas","volume":"69","author":"Kobierzycki","year":"2015","journal-title":"Postepy Hig. Med. Dosw."},{"key":"ref_41","first-page":"1033","article-title":"Angiogenesis, lymphangiogenesis and neurogenesis in endometriosis","volume":"5","author":"Peters","year":"2013","journal-title":"Front. Biosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1095\/biolreprod.115.135780","article-title":"Preeclampsia As modulator of offspring health","volume":"94","author":"Stojanovska","year":"2016","journal-title":"Biol. Reprod."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16027","DOI":"10.1038\/s41598-019-52583-x","article-title":"Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation","volume":"9","author":"Chang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_44","first-page":"e3342","article-title":"Endothelial progenitor cells and cardiovascular correlates","volume":"10","author":"Mudyanadzo","year":"2018","journal-title":"Cureus"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/sctm.19-0242","article-title":"Gestational diabetes impacts fetal precursor cell responses with potential consequences for offspring","volume":"9","author":"Ejarque","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41536-019-0079-2","article-title":"Vegfc\/d-dependent regulation of the lymphatic vasculature during cardiac regeneration is influenced by injury context","volume":"4","author":"Vivien","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e009565","DOI":"10.1161\/JAHA.118.009565","article-title":"Impact of lymphangiogenesis on cardiac remodeling after ischemia and reperfusion injury","volume":"7","author":"Shimizu","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e85096","DOI":"10.1172\/jci.insight.85096","article-title":"Restoration of lymphatic function rescues obesity in Prox1-haploinsufficient mice","volume":"1","author":"Escobedo","year":"2016","journal-title":"JCI Insight"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/ng1642","article-title":"Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity","volume":"37","author":"Harvey","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1038\/npp.2016.158","article-title":"The Role of the Immune System in Autism Spectrum Disorder","volume":"42","author":"Meltzer","year":"2017","journal-title":"Neuropsychopharmacology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1097\/00042737-200508000-00009","article-title":"The significance of ileo-colonic lymphoid nodular hyperplasia in children with autistic spectrum disorder","volume":"17","author":"Wakefield","year":"2005","journal-title":"Eur. J. Gastroenterol.Hepatol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.yexcr.2005.11.012","article-title":"Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis","volume":"312","author":"Shibuya","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1182\/blood-2010-06-291930","article-title":"Gremlin is a novel agonist of the major proangiogenic receptor VEGFR2","volume":"116","author":"Mitola","year":"2010","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"5583","DOI":"10.1002\/jcb.27842","article-title":"Knockdown GREM1 suppresses cell growth, angiogenesis, and epithelial-mesenchymal transition in colon cancer","volume":"120","author":"Liu","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1101\/gad.13.3.295","article-title":"Roles of ephrinB ligands and EphB receptors in cardiovascular development: Demarcation of arterial\/venous domains, vascular morphogenesis, and sprouting angiogenesis","volume":"13","author":"Adams","year":"1999","journal-title":"Genes Dev."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.3389\/fimmu.2019.01473","article-title":"Emerging Roles for Eph Receptors and Ephrin Ligands in immunity","volume":"10","author":"Darling","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3389\/fncel.2017.00323","article-title":"Overlapping Mechanisms of Peripheral Nerve Regeneration and Angiogenesis Following Sciatic Nerve Transection","volume":"11","author":"Wang","year":"2017","journal-title":"Front. Cell Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Wei, L., Sun, C., Zhang, Y., Han, N., and Sun, S. (2020). miR-503\u20135p inhibits colon cancer tumorigenesis, angiogenesis, and lymphangiogenesis by directly downregulating VEGF-A. Gene Ther., 1\u201313.","DOI":"10.1038\/s41434-020-0167-3"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.4049\/jimmunol.0903063","article-title":"B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes","volume":"184","author":"Shrestha","year":"2010","journal-title":"J. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1161\/ATVBAHA.107.150433","article-title":"VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment","volume":"28","author":"Murakami","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2055","DOI":"10.1101\/gad.432007","article-title":"Angiomotin regulates endothelial cell migration during embryonic angiogenesis","volume":"21","author":"Aase","year":"2007","journal-title":"Genes Dev."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1083\/jcb.152.6.1247","article-title":"Angiomotin: An angiostatin binding protein that regulates endothelial cell migration and tube formation","volume":"152","author":"Troyanovsky","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1096\/fj.07-9509com","article-title":"Therapeutic antibodies targeting angiomotin inhibit angiogenesis in vivo","volume":"22","author":"Levchenko","year":"2008","journal-title":"FASEB J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9208","DOI":"10.1073\/pnas.0603110103","article-title":"A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth","volume":"103","author":"Holmgren","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/jcp.21990","article-title":"Thrombospondin type I domain containing 7A (THSD7A) mediates endothelial cell migration and tube formation","volume":"222","author":"Wang","year":"2010","journal-title":"J. Cell Physiol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Kuo, M.W., Wang, C.H., Wu, H.C., Chang, S.J., and Chuang, Y.J. (2011). Soluble THSD7A is an N-glycoprotein that promotes endothelial cell migration and tube formation in angiogenesis. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0029000"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1002\/dvdy.22641","article-title":"Zebrafish Thsd7a is a neural protein required for angiogenic patterning during development","volume":"240","author":"Wang","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12929-016-0277-9","article-title":"Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway","volume":"23","author":"Liu","year":"2016","journal-title":"J. Biomed. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1073\/pnas.0605957104","article-title":"Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor","volume":"104","author":"Crawford","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.brainresbull.2020.12.023","article-title":"Angiopoietin-like 4 promotes angiogenesis and neurogenesis in a mouse model of acute ischemic stroke","volume":"168","author":"Qiu","year":"2021","journal-title":"Brain Res. Bull."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mvr.2009.10.005","article-title":"Semaphorin 5A promotes angiogenesis by increasing endothelial cell proliferation, migration, and decreasing apoptosis","volume":"79","author":"Sadanandam","year":"2010","journal-title":"Microvasc. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1128\/MCB.25.6.2310-2319.2005","article-title":"Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system","volume":"25","author":"Fiore","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2170\/jjphysiol.48.133","article-title":"Basic fibroblast growth factor-mediated lymphangiogenesis of lymphatic endothelial cells isolated from dog thoracic ducts: Effects of heparin","volume":"48","author":"Tan","year":"1998","journal-title":"Jpn. J. Physiol"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1161\/01.RES.0000118600.91698.BB","article-title":"Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability","volume":"94","author":"Cao","year":"2004","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1097\/ICO.0b013e31823f8b5a","article-title":"b-FGF induces corneal blood and lymphatic vessel growth in a spatially distinct pattern","volume":"31","author":"Hajrasouliha","year":"2012","journal-title":"Cornea"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"15894","DOI":"10.1073\/pnas.1208324109","article-title":"Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis","volume":"109","author":"Cao","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"38566","DOI":"10.18632\/oncotarget.9570","article-title":"Basic fibroblast growth factor promotes VEGF-C-dependent lymphangiogenesis via inhibition of miR-381 in human chondrosarcoma cells","volume":"7","author":"Tzeng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3233\/CBM-181466","article-title":"Downregulated GBX2 gene suppresses proliferation, invasion and angiogenesis of breast cancer cells through inhibiting the Wnt\/beta-catenin signaling pathway","volume":"23","author":"Fang","year":"2018","journal-title":"Cancer Biomark"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"ACOG Committee on Obstetric Practice (2002). Practice bulletin #33: Diagnosis and management of preeclampsia and eclampsia. Obstet. Gynecol., 99, 159\u2013167.","DOI":"10.1016\/S0029-7844(01)01747-1"},{"key":"ref_80","unstructured":"American College of Obstreticians and Gynecologists (2013). Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy. Obstet. Gynecol., 122, 1122\u20131131."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1182\/blood-2006-06-029298","article-title":"Receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) increases vascular permeability: Impaired permeability and angiogenesis in eNOS-deficient mice","volume":"109","author":"Min","year":"2007","journal-title":"Blood"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1002\/stem.2003","article-title":"TGFBIp regulates differentiation of EPC (CD133(+) C-kit(+) Lin(-) cells) to EC through activation of the Notch signaling pathway","volume":"33","author":"Maeng","year":"2015","journal-title":"Stem Cells"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.1923","article-title":"Fast gapped-read alignment with Bowtie 2","volume":"9","author":"Langmead","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: A flexible suite of utilities for comparing genomic features","volume":"26","author":"Quinlan","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_85","unstructured":"R Foundation for Statistical Computing (2016). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: Open software development for computational biology and bioinformatics","volume":"5","author":"Gentleman","year":"2004","journal-title":"Genome Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4237\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:49:54Z","timestamp":1760161794000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/4237"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,19]]},"references-count":86,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22084237"],"URL":"https:\/\/doi.org\/10.3390\/ijms22084237","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,19]]}}}