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Whether relative fetal hypoxia during evolution of PPHN renders the fetal brain vulnerable to perinatal brain injury remains unclear. We hypothesized that in utero ductal constriction, which induces PPHN also impairs cerebral angiogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fetal lambs with PPHN induced by prenatal ligation of the ductus arteriosus were compared to gestation matched twin controls. Freshly collected or fixed brain specimens were analyzed by immunohistochemistry, Western blot analysis, and RT\u2010PCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Cortical capillary density was decreased in PPHN lambs compared to controls (Glut\u20101, isolectin B\u20104 and factor VIII, <jats:italic>n<\/jats:italic> = 6, <jats:italic>p<\/jats:italic> &lt; 0.05). Hypoxia inducible factor\u20101\u03b1 (HIF\u20101\u03b1) and vascular endothelial growth factor (VEGF) protein levels were decreased in cortical cell lysates of PPHN lambs. PPHN increased angiopoetin\u20101 (Ang\u20101) and tyrosine\u2010protein kinase receptor (Tie\u20102) protein expression while angiopoetin\u20102 (Ang\u20102) protein levels were decreased (<jats:italic>n<\/jats:italic> = 6, <jats:italic>p<\/jats:italic> &lt; 0.05). PPHN did not change mRNA levels of these proteins significantly (<jats:italic>n<\/jats:italic> = 6).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>PPHN decreased cortical capillary density in fetal lamb brain. PPHN decreased the expression of proteins involved in angiogenesis. These findings suggest that PPHN is associated with impaired cortical angiogenesis.<\/jats:p><\/jats:sec>","DOI":"10.1016\/j.ijdevneu.2014.08.003","type":"journal-article","created":{"date-parts":[[2014,8,27]],"date-time":"2014-08-27T02:16:21Z","timestamp":1409105781000},"page":"113-118","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension"],"prefix":"10.1002","volume":"38","author":[{"given":"Susan S.","family":"Cohen","sequence":"first","affiliation":[{"name":"Department of Pediatrics Children's Research Institute Medical College of Wisconsin Wauwatosa WI 53226 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bethany R.","family":"Powers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Children's Research Institute Medical College of Wisconsin Wauwatosa WI 53226 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Lerch\u2010Gaggl","sequence":"additional","affiliation":[{"name":"Department of Pathology Division of Pediatric Pathology Medical College of Wisconsin Wauwatosa WI 53226 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ru\u2010Jeng","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Children's Research Institute Medical College of Wisconsin Wauwatosa WI 53226 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Girija Ganesh","family":"Konduri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Children's Research Institute Medical College of Wisconsin Wauwatosa WI 53226 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,8,27]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2009.11.010"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/08830738060210070101"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2011.03.016"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6123(08)61419-3"},{"key":"e_1_2_8_6_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1824-7288-36-45","article-title":"High prevalence of minor neurologic deficits in a long\u2010term neurodevelopmental follow\u2010up of children with severe persistent pulmonary hypertension of the newborn: a cohort study","volume":"36","author":"Berti A.","year":"2010","journal-title":"Ital. 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