Loss of mural cell-derived laminin aggravates hemorrhagic brain injury

Abstract

Background: Mural cells synthesize and deposit laminin to the basement membrane. To investigate the function of mural cell-derived laminin, we generated a mutant mouse line lacking mural cell-derived laminin (termed PKO). In a previous study, we showed that the PKO mice were grossly normal under homeostatic condition, but developed blood-brain barrier (BBB) breakdown with advanced age (> 8 months), suggesting that these mutants are intrinsically weak. Based on these findings, we hypothesized that PKO mice have exacerbated injuries in pathological conditions. Methods: Using collagenase-induced intracerebral hemorrhage (ICH) as an injury model, we examined various stroke outcomes, including hematoma volume, neurological function, neuronal death, BBB integrity, paracellular/ transcellular transport, inflammatory cell infiltration, and brain water content, in PKO mice and their wildtype littermates at young age (6-8 weeks). In addition, transmission electron microscopy (TEM) analysis and an in vitro ICH model were used to investigate the underlying molecular mechanisms. Results: Compared to age-matched wildtype littermates, PKO mice display aggravated stroke outcomes, including larger hematoma size, worse neurological function, increased neuronal cell death, enhanced BBB permeability, increased transcytosis, and elevated inflammatory cell infiltration. These mutants also exhibit high baseline brain water content independent of aquaporin-4 (AQP4). In addition, mural cell-derived laminin significantly reduced caveolin-1 without affecting tight junction proteins in the in vitro ICH model. Conclusions: These results suggest that mural cell-derived laminin attenuates BBB damage in ICH via decreasing caveolin-1 and thus transcytosis, regulates brain water homeostasis, and plays a beneficial role in ICH.

Structural and Functional Remodeling of the Brain Vasculature Following Stroke

“…The phenotype presented by the transgenic animals appears similar to abnormalities found in human hypertensive hemorrhagic patients in the striatum (Chen et al, 2013). More recently, Gautam et al (2020) demonstrated in mutant mice lacking mural cell-derived laminin that the latter attenuates BBB damage in ICH via decreasing caveolin-1 and transcytosis.…”

“…-VEGF can also increase BBB permeability, which may help peripheral macrophages infiltrate into the brain. Manoonkitiwongsa et al, 2001;Gould et al, 2006;Chen et al, 2013;Fu et al, 2014;Lan et al, 2017;Zhang et al, 2017;Gautam et al, 2020;Mechtouff et al, 2020.…”

Angiogenesis and Blood-Brain Barrier Permeability in Vascular Remodeling after Stroke

“…Low rate of vesicular transport (transcytosis) has been identified as one of the two unique properties of CNS ECs that maintain the restrictive quality of the BBB [ 34 ]. Loss of PCs increased transcytosis and enhanced BBB permeability in mouse model of intracerebral hemorrhage [ 35 ] and in pericytic-laminin conditional knockout mouse [ 36 ]. Microglia, the brain resident immune cells, are activated in response to injury and orchestrate the brain’s inflammatory response [ 37 ].…”

Intermittent hypoxia mimicking obstructive sleep apnea aggravates early brain injury following ICH via neuroinflammation and apoptosis

“…However, long-term outcomes were found to not be altered, and it rarely affects neurological recovery (10). increasing numbers of studies have found that red blood cell debris (hemoglobin and its degradation products) and other blood components trigger secondary brain injury following icH and contribute to a series of damaging events, including neuroinflammation, brain edema, oxidative stress, blood-brain barrier (BBB) damage and neuronal death (11)(12)(13)(14)(15)(16). an increasing number of studies has been investigated the mechanisms underlying icH-induced secondary injury to identify improved therapeutic targets for icH; the potential mechanisms underlying eBi include autophagy, apoptosis, direct neuronal death and necroptosis (13,17,18).…”