White matter abnormalities are a central feature of cerebral small vessel disease (cSVD) and underpin cognitive impairment and dementia but their mechanistic link remains poorly understood. To provide insight we studied mice (Col4a1+/Svc) with a mutation in the gene Col4a1 as an established model of cSVD due to collagen IV mutations. Since collagen IV is a key component of the basement membrane, a specialised extracellular matrix structure (ECM), we hypothesised that the Col4a1 mutation would disrupt the ECM and cause white matter abnormalities. Microstructural alterations in white matter were assessed using Magnetic Resonance diffusion tensor imaging (MR-DTI) in parallel with pathology and ultrastructural investigations of white matter. We determined that myelinating oligodendrocyte pools were reduced in parallel with prominent alterations in myelinated axons and white matter structural integrity in Col4a1+/Svc mice. Proteomic analysis of white matter revealed a significant number (n=176) of differentially expressed proteins in Col4a1+/Svc compared to controls. In particular pathways relating to the ECM and the endoplasmic reticulum (ER), including ER stress, were affected. We exploited this in a pre-clinical intervention study using the FDA-approved chemical chaperone 4-phenylbutyrate (PBA) to promote protein trafficking and reduce ER stress. PBA treatment in Col4a1+/Svc mice conferred protection against white matter defects (increasing myelinating oligodendrocytes and improving axon-glial integrity) compared to untreated Col4a1+/Svc mice. These data provide novel insight into the diversity of pathomolecular mechanisms of white matter abnormalities in cSVD and identify a modifiable pathway as a putative therapeutic target for cSVD.