Abstract
Vascular smooth muscle cells (SMCs) undergo a series of dramatic changes in CADASIL, the most common inherited cause of vascular dementia and stroke. NOTCH3 protein accumulates and aggregates early in CADASIL, followed by loss of mature SMCs from the media of brain arteries and marked intimal proliferation. Similar intimal thickening is seen in peripheral arterial disease, which features pathological intimal cells including proliferative, dedifferentiated, smooth muscle-like cells deficient in SMC markers. Limited studies have been performed to investigate the differentiation state and location of SMCs in brain vascular disorders. Thus, we investigated the distribution of cells expressing SMC markers in a group of genetically characterized, North American CADASIL brains. We quantified brain RNA abundance of these markers in nine genetically verified cases of CADASIL and found that mRNA expression for several mature SMC markers was increased in CADASIL brain compared to age-matched control. Immunohistochemical studies and in situ hybridization localization of mRNA demonstrated loss of SMCs from the arterial media, and SMC marker-expressing cells were instead redistributed into the intima of diseased arteries and around balloon cells of the degenerating media. We conclude that, despite loss of medial smooth muscle cells in diseased arteries, smooth muscle markers are not lost from CADASIL brain, but rather, the localization of cells expressing mature SMC markers changes dramatically.