Pathogenesis and prevention of intraventricular hemorrhage

Abstract

Intraventricular hemorrhage (IVH) is a major neurologic complication of prematurity. Pathogenesis of IVH is attributed to intrinsic fragility of germinal matrix vasculature and to the fluctuation in the cerebral blood flow. Germinal matrix exhibits rapid angiogenesis orchestrating formation of immature vessels. Prenatal glucocorticoid exposure remains the most effective means of preventing IVH. Therapies targeted to enhance the stability of the germinal matrix vasculature and minimize fluctuation in the cerebral blood flow might lead to more effective strategies in preventing IVH.

Keywords: Angiogenesis; Astrocytes; Germinal matrix hemorrhage; Glucocorticoids; Indomethacin; Intraventricular hemorrhage; Pericytes; Premature infants.

Figure 1. Morphology of germinal matrix

A) Representative cresyl violet staining of coronal section of the right-sided cerebral hemisphere of a 23 week preterm infant. Note cortical plate (arrows) and germinal matrix (arrow heads). Germinal matrix (violet staining) surrounds the whole ventricle, but is most conspicuous at the head of caudate nucleus. V, ventricle. Scale bar, 0.5 cm. B) Representative immunofluorescence of cryosection from germinal matrix of a 23 week premature infant labeled with DAPI (blue), GFAP (green), and laminin (vascular marker, red). Note germinal matrix is highly vascular (vascular endothelium in red) and enriched with GFAP (+) glial cells (green). C) Coronal brain section was double labeled with nestin (progenitor cells, green), Sox2 (radial glia, blue), and Ki67 (red, proliferation marker). Note nestin and Sox2 positive cells are abundant in the germinal matrix. Scale bar; 100 (B) and 50 μm (C). D) Schematic drawing of the blood brain barrier in cross section showing endothelium, endothelial tight junction, basal lamina, pericyte, and astrocyte endfeet.

Figure 2

Electron micrograph showing endothelium (arrow heads) and pericyte (white arrows) separated by basal laminia (black arrows) in the white matter of 3 day old preterm rabbit pup (E29). Note pericyte wraps around the endothelium and is outer to the basal lamina. Scale bar, 4 μm.

Figure 3. Germinal matrix vasculature is deficient in fibronectin and lack GFAP+ astrocyte endfeet coverage

A) Representative immunofluorescence of cryosection from germinal matrix and white matter of a 24 week premature human infant labeled with fibronectin (red) specific antibody. Fibronectin is strongly expressed in the white matter whereas it is weakly expressed in the germinal matrix (arrowheads). Scale bar; 20μm. B) Cryosection from germinal matrix and white matter of a 24 week premature infant was double-labeled with CD34 (endothelium, red) and GFAP (astrocyte, green) specific antibody. GFAP positive astrocyte endfeet are intimately associated with the outer endothelial surface in the white matter (arrowheads). However, GFAP positive astrocytes are not covering endothelium in the germinal matrix (arrows).

Figure 4. Mechanisms underlying fragility of germinal matrix vasculature

Hypoxic germinal matrix triggers upregulation of VEGF and angiopoieitn-2 expression. These growth factors induce angiogenesis. The angiogenic vessels of the germinal matrix exhibit paucity of pericytes and deficiency of fibronectin in immature basal lamina. Additionally, astrocyte endfeet in the germinal matrix vasculature display reduced expression of GFAP. These factors contribute to the fragility of the germinal matrix.