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

The extracellular matrix (ECM), primarily composed of collagen, offers critical structural and mechanical foundations for all multicellular organisms. It plays an influential role in determining cellular activities, including cell growth, programmed cell death, morphology, movement, and differentiation. Specialized ECM structures known as basement membranes (BMs) coat most layers of epithelial and endothelial cells. Beyond their foundational and partitioning roles, BMs and their constituents participate in diverse biological signaling pathways, growth processes, and disease developments. Collagen XVIII is a well-conserved component within BMs throughout evolutionary history. This multi-domain heparan sulfate proteoglycan (HSPG) is manifested in three distinct tissue-specific forms. All three versions of collagen XVIII feature Endostatin, their C-terminal domain, known for its anti-angiogenic attributes. Earlier research on collagen IV, another primary BM element, highlighted pathological modifications in small arteries and capillaries in the absence of collagen IV in mice. These changes echo those seen in cerebral small vessel disease (CSVD), such as age-related blood-brain barrier (BBB) deffects and restructuring of the vessel wall, which can lead to vessel blockages and surrounding bleeds. CSVD stands as a primary contributor to vascular cognitive issues, playing a role in numerous neurological conditions, from strokes and mild cognitive deficits to dementia. A key objective of this thesis was to investigate if deletion of the collagen XVIII may results in development of CSVD-like pathology in terms of microvascular and neuroinflammatory alterations, and remodelling of perivascular, perineuronal and perisynaptic ECM. Based on our observations, Col18a1-/- mice at 5 months of age exhibited an increased BBB permeability to mouse IgG in deep gray matter regions. There were noticeable accumulations of intravascular erythrocytes in capillaries and arterioles located in the cortex, hippocampus, and deep gray matter, ...