Cerebral Vascular Dysfunction in Humanized ApoE4 Knock-In Mice

Background: Cerebrovascular dysfunction disrupts cerebral blood flow (CBF) regulation and contributes to the pathogenesis of Alzheimer’s disease (AD) and related dementias. Clinical evidence shows that individuals carrying the Apolipoprotein E4 (ApoE4) allele, the strongest genetic risk factor for AD, demonstrate early alterations in CBF compared to non-carriers. However, the mechanisms underlying vascular dysfunction among ApoE4 carriers remain incompletely understood. Pial arteries contribute to CBF regulation, accounting for over 40% of the brain’s total vascular resistance. Brain vascular resistance, in turn, is dependent on the activity of L-type voltage-gated calcium channels (CaV1.2) in vascular smooth muscle cells (VSMCs). Previous findings from our laboratory show that CaV1.2 activity is diminished in the brain microcirculation of humanized ApoE4 knock-in (hApoE4-KI) mice, resulting in reduced contractile function of cerebral arterioles. Whether the expression of ApoE4 impairs the contractile function of cerebral pial arteries remains unknown. Hypothesis: We hypothesize that ApoE4 expression decreases CaV1.2 channel activity in pial artery VSMCs of hApoE4-KI mice, resulting in diminished contractile function and hemodynamic control in the brain. Methods: To test this hypothesis, we assessed the contractile function of freshly isolated posterior communicating arteries (PComAs) from hApoE4-KI and hApoE3-KI (control) mice using pressure myography and, using patch-clamp electrophysiology, measured CaV1.2 channel activity in freshly isolated cerebral artery VSMCs. Results: Whole cell patch clamp recordings showed significantly reduced CaV1.2 channel currents in isolated VSMC from hApoE4-KI mice compared to hApoE3-KI controls. Similarly, we observed diminished contractile responses of PComAs from hApoE4-KI mice when exposed to 60 mM potassium chloride and 300 nM FPL 64176, a potent CaV1.2 channel agonist. Conclusion: Together, these data suggest that ApoE4 expression reduces CaV1.2 channel activity and consequently diminishes the contractility of mouse cerebral pial arteries. Nevertheless, the mechanisms underlying CaV1.2 channel dysfunction in hApoE4-KI mouse cerebral arteries remain unknown and represent an area for further investigation. Funding: National Institutes of Health (R01 AG073230) and American Physiological Society’s Summer Undergraduate Research Fellowship (SURF). This abstract was presented at the American Physiology Summit 2026 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.