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Impaired cerebral angiogenesis in the fetal lamb model of persistent pulmonary hypertension. Int J Dev Neurosci 2014 Nov;38:113-8



Pubmed ID


Pubmed Central ID




Scopus ID

2-s2.0-84907848489   1 Citation


BACKGROUND: Persistent pulmonary hypertension of the newborn (PPHN) is associated with increased risk of neuro-developmental impairments. 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.

METHODS: 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-PCR.

RESULTS: Cortical capillary density was decreased in PPHN lambs compared to controls (Glut-1, isolectin B-4 and factor VIII, n=6, p<0.05). Hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels were decreased in cortical cell lysates of PPHN lambs. PPHN increased angiopoetin-1 (Ang-1) and tyrosine-protein kinase receptor (Tie-2) protein expression while angiopoetin-2 (Ang-2) protein levels were decreased (n=6, p<0.05). PPHN did not change mRNA levels of these proteins significantly (n=6).

CONCLUSIONS: 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.

Author List

Cohen SS, Powers BR, Lerch-Gaggl A, Teng RJ, Konduri GG


Susan Cohen MD Associate Professor in the Pediatrics department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Ru-Jeng Teng MD Associate Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cerebral Cortex
Cyclooxygenase 2
Disease Models, Animal
Embryo, Mammalian
Gene Expression Regulation, Developmental
Hypoxia-Inducible Factor 1, alpha Subunit
Neovascularization, Pathologic
Persistent Fetal Circulation Syndrome
Sheep, Domestic
Vascular Endothelial Growth Factor A
jenkins-FCD Prod-480 9a4deaf152b0b06dd18151814fff2e18f6c05280