Early ensheathing pericyte dysfunction in a mouse model of CADASIL

Small vessel disease (SVD) of the brain underlies 25% of stroke cases and is the most common cause of vascular cognitive impairment. The most common monogenic form of SVD is CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), caused by mutations of the NOTCH3 protein which is widely expressed in mural cells (vascular smooth muscle cells [SMCs] and pericytes), although little is known regarding pericyte pathology in this disease. Pericytes proximal to the penetrating arteriole (PA), known as ensheathing pericytes, contract and relax to rapidly regulate capillary diameter and thus blood flow in the downstream capillary tree. We conducted two-photon laser scanning microscopy of blood flow and pericyte contractile responses with CADASIL Notch3 R169C transgenic and control mice. Our data indicate that ensheathing pericyte responses to capillary electrical signals are impaired prior to other known CBF deficits, thus raising the tantalizing possibility that ensheathing pericytes could be a target for early clinical intervention in CADASIL. We also show that thin-strand pericyte K ATP and endothelial K IR -mediated electrical signals to PA SMCs are intact at this early time point before their breakdown later in CADASIL pathology. Taken together, this work provides a new candidate mechanism by which CBF is diminished early in CADASIL pathogenesis for potential therapeutic intervention. NINDS F31NS139505-01 R01NS138179 CP2-1-0000000385 R01AG066645 DP2OD02944801 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.