Microvascular damage, neuroinflammation and extracellular matrix remodeling in Col18a1 knockout mice as a model for early cerebral small vessel disease

Abstract

Collagen XVIII (COL18A1) is an abundant heparan sulfate proteoglycan in vascular basement membranes. Here, we asked (i) if the loss of collagen XVIII would result in blood-brain barrier (BBB) breakdown, pathological alterations of small arteries and capillaries and neuroinflammation as found in cerebral small vessel disease (CSVD) and (ii) if such changes may be associated with remodeling of synapses and neural extracellular matrix (ECM). We found that 5-month-old Col18a1-/- mice had elevated BBB permeability for mouse IgG in the deep gray matter, and intravascular erythrocyte accumulations were observed in capillaries and arterioles in the cortex, hippocampus, and deep gray matter, with a lesser accumulation in the white matter. The permeability of the BBB increased with age in Col18a1-/- mice and affected cortical regions and the hippocampus in mice aged 12 months. However, none of the Col18a1-/- mice displayed hallmarks typical of more advanced stages of CSVD, such as perivascular space enlargement or large bleeds or infarcts. Collagen XVIII deficiency-induced BBB leakage was accompanied by activation of microglia and astrocytes, a loss of aggrecan in the ECM of perineuronal nets associated with fast-spiking inhibitory interneurons and accumulation of the perisynaptic ECM proteoglycan brevican and the microglial complement protein C1q at excitatory synapses. As the pathway underlying these regulations, we found increased signaling through the TGF-ß1/Smad3/TIMP-3 cascade. Thus, collagen XVIII proved to be crucial for the structural integrity of small vessels and its absence leads to pathological changes typical of early stages of CSVD. Furthermore, this study highlights an association between the alterations of perivascular ECM, extracellular proteolysis, and perineuronal/perisynaptic ECM, as a possible substrate of synaptic and cognitive alterations in CSVD.

Zerebrale Mikroangiopathie: Fortschritte im Verständnis der Pathophysiologie

“…Die Folgen sind Neuroinflammation und der Umbau von vaskulärer und neuraler EZM, die wiederum zu strukturellen Gefäßwandveränderungen und einem Verlust an synaptischer Plastizität führen. Letzterer könnte einen biologischen Erklärungsansatz für kognitive Defizite und Demenzentwicklung liefern [29][30].…”