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Chronic intrauterine fetal hypoxia, such as occurs in intrauterine growth restriction (IUGR) is likely to lead to a reduction in oxygen delivery to the brain and long\u2010term neurological abnormalities. Thus we investigated whether vascular remodeling and vascular abnormalities were evident in the brain of IUGR newborn lambs that were chronically hypoxic in utero. Single uterine artery ligation (SUAL) surgery was performed in fetuses at \u223c105 days gestation (term \u223c145 days) to induce placental insufficiency and IUGR. Ewes delivered naturally at term and lambs were euthanased 24 h later. IUGR brains (<jats:italic>n<\/jats:italic> = 9) demonstrated a significant reduction in positive staining for the number of blood vessels (laminin immunohistochemistry) compared with control (<jats:italic>n<\/jats:italic> = 8): from 1650 \u00b1 284 to 416 \u00b1 47 cells\/mm<jats:sup>2<\/jats:sup> in subcortical white matter (SCWM) 1793 \u00b1 298 to 385 \u00b1 20 cells\/mm<jats:sup>2<\/jats:sup> in periventricular white matter (PVWM), and 1717 \u00b1 161 to 405 \u00b1 84 cells\/mm<jats:sup>2<\/jats:sup> in the subventricular zone (SVZ). The decrease in vascular density was associated with a significant decrease in VEGF immunoreactivity. The percentage of blood vessels exhibiting endothelial cell proliferation (Ki67 positive) varied regionally between 14 to 22% in white matter of control lambs, while only 1\u20133% of blood vessels in IUGR brains showed proliferation. A 66% reduction in pericyte coverage (\u03b1\u2010SMA and desmin) of blood vessels was observed in SCWM, 71% in PVWM, and 73% in SVZ of IUGR lambs, compared to controls. A reduction in peri\u2010vascular astrocytes (GFAP and laminin) was also observed throughout the white matter of IUGR lambs, and extravasation of albumin into the brain parenchyma was present, indicative of increased permeability of the blood brain barrier. Chronic hypoxia associated with IUGR results in a reduction in vascular density in the white matter of IUGR newborn brains. Vascular pericyte coverage and peri\u2010vascular astrocytes, both of which are essential for stabilisation of blood vessels and the maintenance of vascular permeability, were also decreased in the white matter of IUGR lambs. In turn, these vascular changes could lead to inadequate oxygen supply and contribute to under\u2010perfusion and increased vulnerability of white matter in IUGR infants.<\/jats:p>","DOI":"10.1016\/j.ijdevneu.2015.01.004","type":"journal-article","created":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T17:15:51Z","timestamp":1422551751000},"page":"55-65","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Cerebrovascular adaptations to chronic hypoxia in the growth restricted lamb"],"prefix":"10.1002","volume":"45","author":[{"given":"Margie","family":"Castillo\u2010Melendez","sequence":"first","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Yawno","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beth J.","family":"Allison","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Jenkin","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"},{"name":"Department of Obstetrics &amp; Gynaecology Southern Clinical School Monash University Clayton Victoria 3800 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euan M.","family":"Wallace","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"},{"name":"Department of Obstetrics &amp; Gynaecology Southern Clinical School Monash University Clayton Victoria 3800 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne L.","family":"Miller","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, MIMR\u2010PHI 27\u201031 Wright St Clayton Victoria 3168 Australia"},{"name":"Department of Obstetrics &amp; Gynaecology Southern Clinical School Monash University Clayton Victoria 3800 Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.4155\/tde.11.23"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2012.191"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2012.09.007"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.0000254729.27386.05"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2003.12.016"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1215\/S1152851705000232"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-199801000-00005"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.000531"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3281-07.2007"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00487.2013"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077377"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.2000.89.5.1937"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.22.12081"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1979.sp012847"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031497"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(86)90128-7"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-003-0745-x"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1067\/mob.2003.384"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.26.11.2120"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8749.1990.tb08116.x"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.57.2.4"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.3.543"},{"key":"e_1_2_8_24_1","first-page":"H1069","article-title":"Cerebrovascular autoregulation during fetal development in sheep","volume":"266","author":"Helou S.","year":"1994","journal-title":"Am. 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