Abstract
Background: Periventricular white matter damage (PWMD), also termed periventricular leukomalacia, is the predominant neurologic lesion in preterm infants. It appears to relate in part to the development of the vascular supply to the cerebral white matter. We investigated whether, in case of severe hypoxia-ischemia, the vascular system would be subject to severe damage or remodeled.
Aims: To evaluate microvessel density (MVD) and the use of ephrinB2 and its receptor EphB4 to mark arterioles and venules to establish the correct anatomic assignment of the remodeled vessels in a hypoxia-induced PWMD rat model.
Methods: Postnatal day 3 rats underwent permanent ligation of the right common carotid artery followed by 6% O2 for 4 h (hypoxia-ischemia) or sham operation and normoxic exposure (sham). MVD and levels of ephrinB2 and EphB4, which are respectively regarded as relatively specific molecular markers of arteries and veins, were determined at postnatal day 7.
Results: Compared with sham rats, MVD, ephrinB2 and EphB4 levels were higher in the brains of hypoxic-ischemic rats. Similar percentages of vessels expressed ephrinB2 and EphB4 in sham rats, but expression of ephrinB2 was greater in brains injured by hypoxia-ischemia.
Conclusions: Following hypoxic-ischemic injury to the rat brain, microvessels were remodeled and more arterioles than venules were acquired.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (81370739) and the Science and Innovation Funds of Jiangsu Province (CXLX12_0123).
References
[1] Allin M, Walshe M, Fern A, Nosarti C, Cuddy M, Rifkin L, et al. Cognitive maturation in preterm and term born adolescents. J Neurol Neurosur Psychiatry. 2008;79:381–6.10.1136/jnnp.2006.110858Search in Google Scholar
[2] Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, et al. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci. 2002;22:455–63.10.1523/JNEUROSCI.22-02-00455.2002Search in Google Scholar
[3] Bayless S, Stevenson J. Executive functions in school-age children born very prematurely. Early Hum Dev. 2007;83: 247–54.10.1016/j.earlhumdev.2006.05.021Search in Google Scholar
[4] Crnkovic S, Hrzenjak A, Marsh LM, Olschewski A, Kwapiszewska G. Origin of neomuscularized vessels in mice exposed to chronic hypoxia. Resp Physiol Neurobiol. 2011;179:342–5.10.1016/j.resp.2011.09.016Search in Google Scholar
[5] Ehlken C, Martin G, Lange C, Gogaki EG, Fiedler U, Schaffner F, et al. Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy. Acta Ophthalmol. 2011;89:82–90.10.1111/j.1755-3768.2009.01609.xSearch in Google Scholar
[6] Fan YF, Shen FX, Frenzel T, Zhu W, Ye JQ, Liu JR, et al. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010;67:488–97.10.1002/ana.21919Search in Google Scholar
[7] Gerety SS, Wang HU, Chen ZF, Anderson DJ. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell. 1999;4:403–14.10.1016/S1097-2765(00)80342-1Search in Google Scholar
[8] Goldshmit Y, McLenachan S, Turnley A. Roles of Eph receptors and ephrins in the normal and damaged adult CNS. Brain Res Rev. 2006;52:327–45.10.1016/j.brainresrev.2006.04.006Search in Google Scholar PubMed
[9] Guo X, Liu L, Zhang M, Bergeron A, Cui Z, Dong J, et al. Correlation of CD34(+) cells with tissue angiogenesis after traumatic brain injury in a rat model. J Neurotrauma. 2009;26:1337–44.10.1089/neu.2008.0733Search in Google Scholar PubMed PubMed Central
[10] Hamada K, Oike Y, Ito Y, Maekawa H, Miyata K, Shimomura T, et al. Distinct roles of ephrin-B2 forward and ephB4 reverse signaling in endothelial cells. Arterioscler Throm Vasc Biol. 2003;23:190–7.10.1161/01.ATV.0000055440.89758.C2Search in Google Scholar PubMed
[11] Heroult M, Schaffner F, Pfaff D, Prahst C, Kirmse R, Kutschera S, et al. EphB4 promotes site-specific metastatic tumor cell dissemination by interacting with endothelial cell-expressed ephrinB2. Mol Cancer Res. 2010;8:1297–309.10.1158/1541-7786.MCR-09-0453Search in Google Scholar
[12] Huang X, Yamada Y, Kidoya H, Naito H, Nagahama Y, Kong L, et al. EphB4 overexpression in B16 melanoma cells affects arterial-venous patterning in tumor angiogenesis. Cancer Res. 2007;67:9800–8.10.1158/0008-5472.CAN-07-0531Search in Google Scholar
[13] Kudo TA, Muto A, Maloney SP, Pimiento JM, Bergaya S, Fitzgerald TN, et al. Venous identity is lost but arterial identity is not gained during vein graft adaptation. Arterioscler Thromb Vasc Biol. 2007;27:1562–71.10.1161/ATVBAHA.107.143032Search in Google Scholar
[14] Kume T. Specification of arterial, venous, and lymphatic endothelial cells during embryonic development. Histol Histopathol. 2010;25:637–46.Search in Google Scholar
[15] Kumral A, Baskin H, Yesilirmak DC, Ergur BU, Aykan S, Genc S, et al. Erythropoietin attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neonatology. 2007;92:269–78.10.1159/000105493Search in Google Scholar
[16] Johnson S, Marlow N. Positive screening results on the modified checklist for autism in toddlers: implications for very preterm populations. J Pediatr. 2009;154:478–80.10.1016/j.jpeds.2008.11.028Search in Google Scholar
[17] Lackmann M, Boyd AW. Eph, a protein family coming of age: more confusion, insight, or complexity? Sci Signal. 2008;1:re2.10.1126/stke.115re2Search in Google Scholar
[18] Larroque B, Ancel PY, Marret S, Marchand L, Andre M, Arnaud C, et al. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet. 2008;371:813–20.10.1016/S0140-6736(08)60380-3Search in Google Scholar
[19] Li ZQ, Gong LL, Wen ZH, Wang J, Xu CS, Huang XD. Delta-like ligand 4 correlates with endothelial proliferation and vessel maturation in human malignant glioma. Onkologie. 2012;35:763–8.10.1159/000345116Search in Google Scholar PubMed
[20] Liu XB, Shen Y, Plane JM, Deng WB. Vulnerability of premyelinating oligodendrocytes to white-matter damage in neonatal brain injury. Neurosci Bull. 2013;29:229–38.10.1007/s12264-013-1311-5Search in Google Scholar PubMed PubMed Central
[21] Okada S, Makino H, Nagumo A, Sugisawa T, Fujimoto M, Kishimoto I, et al. Circulating CD34-positive cell number is associated with brain natriuretic peptide level in type 2 diabetic patients. Diabetes Care. 2008;31:157–8.10.2337/dc07-1125Search in Google Scholar PubMed
[22] Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10:165–80.10.1038/nrc2806Search in Google Scholar
[23] Reissenweber B, Mosch B, Pietzsch J. Experimental hypoxia does not influence gene expression and protein synthesis of Eph receptors and ephrin ligands in human melanoma cells in vitro. Melanoma Res. 2013;23:85–5.10.1097/CMR.0b013e32835e58f3Search in Google Scholar
[24] Taylor AC, Mendel TA, Mason KE, Degen KE, Yates PA, Peirce SM. Attenuation of Ephrinb2 reverse signaling decreases vascularized area and preretinal vascular tuft formation in the murine model of induced retinopathy. Invest Ophth Vis Sci. 2012;53:5462–70.10.1167/iovs.11-8599Search in Google Scholar
[25] Tu YY, He SM, Fu JF, Li G, Xu RX, Lu HL, et al. Expression of EphrinB2 and EphB4 in glioma tissues correlated to the progression of glioma and the prognosis of glioblastoma patients. Clin Transl Oncol. 2012;14:214–20.10.1007/s12094-012-0786-2Search in Google Scholar
[26] Vadivel A, van Haaften T, Alphonse RS, Rey-Parra GJ, Ionescu L, Haromy A, et al. Critical role of the axonal guidance cue Ephrinb2 in lung growth, angiogenesis, and repair. Am J Resp Crit Care. 2012;185:564–74.10.1164/rccm.201103-0545OCSearch in Google Scholar
[27] Volpe JJ. Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res. 2001;50:553–62.10.1203/00006450-200111000-00003Search in Google Scholar
[28] Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8:110–24.10.1016/S1474-4422(08)70294-1Search in Google Scholar
[29] Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell. 1998;93:741–53.10.1016/S0092-8674(00)81436-1Search in Google Scholar
[30] Zhu L, Bai X, Wang S, Hu Y, Wang T, Qian L, et al. Rh-EPO augments angiogenic responses in a neonatal rat model of cerebral unilateral hypoxia-ischemia. Neonatology. 2014;106:143–8.10.1159/000362262Search in Google Scholar PubMed
[31] Zhu LH, Jiang L, Zhang ZH, Zhu H. Cerebral white matter injury induced by hypoxic-ischemia and neurological dysfunction in neonatal rats. J Clin Pediatr. 2007;25:784–7.Search in Google Scholar
The authors stated that there are no conflicts of interest regarding the publication of this article.
©2015 by De Gruyter
Articles in the same Issue
- Frontmatter
- Highlight: Diabetes
- Editorial
- Can we really diagnose diabetes during pregnancy?
- First trimester prediction of maternal glycemic status
- Prepregnancy maternal obesity and fetal-perinatal death in a Mediterranean country
- Incorporating first trimester analytes to predict delivery of a large for gestational infant in women with impaired glucose tolerance
- Cord blood galectin-1 and -3 concentrations in term pregnancies with normal restricted and increased fetal growth
- The interplay between maternal obesity and gestational diabetes mellitus
- Ramadan fasting and pregnancy: implications for fetal development in summer season
- Omentin, an adipokine with insulin-sensitizing properties, is negatively associated with insulin resistance in normal gestation
- Reproducibility of a 75G oral glucose tolerance test in pregnant women
- Maternal and fetal factors which influence cord blood glucose levels in term infants delivered by cesarean section
- Original articles
- Risk for fetal loss and prematurity after 12,413 second trimester amniocenteses in a single center
- Non-immune hydrops fetalis as a diagnostic and survival problems: what do we tell the parents?
- Sensitivity of multiple first trimester sonomarkers in fetal aneuploidy detection
- Expression of ephrinB2 and EphB4 in a neonatal rat model of periventricular white matter damage
- Letter to the Editor
- Glucose measurements and gold standards
- Congress Calendar
- Congress Calendar
Articles in the same Issue
- Frontmatter
- Highlight: Diabetes
- Editorial
- Can we really diagnose diabetes during pregnancy?
- First trimester prediction of maternal glycemic status
- Prepregnancy maternal obesity and fetal-perinatal death in a Mediterranean country
- Incorporating first trimester analytes to predict delivery of a large for gestational infant in women with impaired glucose tolerance
- Cord blood galectin-1 and -3 concentrations in term pregnancies with normal restricted and increased fetal growth
- The interplay between maternal obesity and gestational diabetes mellitus
- Ramadan fasting and pregnancy: implications for fetal development in summer season
- Omentin, an adipokine with insulin-sensitizing properties, is negatively associated with insulin resistance in normal gestation
- Reproducibility of a 75G oral glucose tolerance test in pregnant women
- Maternal and fetal factors which influence cord blood glucose levels in term infants delivered by cesarean section
- Original articles
- Risk for fetal loss and prematurity after 12,413 second trimester amniocenteses in a single center
- Non-immune hydrops fetalis as a diagnostic and survival problems: what do we tell the parents?
- Sensitivity of multiple first trimester sonomarkers in fetal aneuploidy detection
- Expression of ephrinB2 and EphB4 in a neonatal rat model of periventricular white matter damage
- Letter to the Editor
- Glucose measurements and gold standards
- Congress Calendar
- Congress Calendar