Cerebral microbleeds in a neonatal rat model.
In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter.



Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks.



mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls.



In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development.
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Brianna C
BC
Theriault
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Seung Kyoon
SK
Woo
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Jason K
JK
Karimy
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Kaspar
K
Keledjian
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Jesse A
JA
Stokum
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Amrita
A
Sarkar
Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Turhan
T
Coksaygan
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Svetlana
S
Ivanova
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
Volodymyr
V
Gerzanich
Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.|Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
J Marc
0000-0002-5373-1988
JM
Simard
D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000473:pathology*; D007150:Immunohistochemistry; D020300:Intracranial Hemorrhages / Q000473:pathology*; D007511:Ischemia / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
D008070:Lipopolysaccharides