Introduction: Laminin, a major component of the basement membrane, exists in many isoforms. Although loss of laminin is found in intracerebral hemorrhage (ICH), the exact biological function of laminin in ICH remains largely unknown. This is primarily due to its intrinsic complexity (various isoforms) and the lack of genetic tools. In a previous study, we generated a transgenic line with laminin deficiency specifically in pericytes (PKO). These PKO mice are grossly normal in pure C57Bl6 background at young age, although mild blood brain barrier (BBB) breakdown is detected in aged mutants. In this study, we aim to investigate the role of pericyte-derived laminin in brain pathology and disease progression in ICH.
Methods: Collagenase was injected into the striatum of young (2-month-old) control and PKO mice to induce hemorrhage. At 2, 5, and 14 days post injury (dpi), hematoma size, neuronal death, vascular permeability, inflammatory cell infiltration, and neurological deficits were examined.
Results: Compared to the controls, the PKO mice showed larger hematoma and increased neuronal deaths at 2 and 5 dpi, but more severe neurological deficits at 14 dpi. Additionally, substantially increased IgG level was found in PKO brains at 14 dpi, indicating BBB integrity disruption. Consistent with this observation, significantly higher levels of CD45+ leukocytes and Ly6G+ granulocytes were detected in PKO brains at 14 dpi. Similarly, elevated CD3 staining was found in PKO brains at 5 and 14 dpi. These data suggest that the recovery of vascular integrity after ICH is delayed in PKO mice. Moreover, PKO brains also showed increased number of CD11b+ microglia/macrophages at all three time points examined, suggesting a possible role of pericyte-derived laminin in microglia/macrophage activation and/or migration.
Conclusion: Our data support a neuroprotective role of pericyte-derived laminin in ICH. This beneficial effect is probably due to its biological activities in: (1) promoting neuronal survival; (2) stabilizing newly formed vessels and enhancing their integrity; (3) inhibiting inflammatory cell infiltration; and (4) regulating the activation and/or migration of microglia/macrophages.