Date Published: February 3, 2017
Publisher: Public Library of Science
Author(s): Brianna Carusillo Theriault, Seung Kyoon Woo, Jason K. Karimy, Kaspar Keledjian, Jesse A. Stokum, Amrita Sarkar, Turhan Coksaygan, Svetlana Ivanova, Volodymyr Gerzanich, J. Marc Simard, Thiruma V. Arumugam.
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.
In adult humans, “cerebral microbleeds” (brain microbleeds, microhemorrhages, punctate hemorrhages) are increasingly diagnosed using susceptibility-weighted magnetic resonance imaging (MRI), are frequently associated with white matter abnormalities (leukoaraiosis), and are increasingly recognized to play important roles in several neurodegenerative diseases [1–5].
The principal findings of the present study are that, in a rat model: (i) an angiogenenic response induced shortly before birth can predispose to cerebral microbleeds during birth; (ii) microbleeds can damage white matter, especially if they occur during the stage of white matter development dominated by pre-OLs; (iii) in rats, white matter damage induced by microbleeds sustained at birth is accompanied by severe axonopathy and severe adolescent neurological dysfunction, reminiscent of periventricular leukomalacia in humans; (iv) when microbleeds in susceptible animals are reduced, e.g., by abdominal delivery, significantly better myelination, axonal preservation, and neurological function are observed, regardless of potentially harmful prenatal exposures.