Profound decrease in myogenic tone of parenchymal arterioles in a genetic model of cerebral ischemic small vessel disease

Abstract

Dominant mutations in NOTCH3 gene induce the most common heritable cause of stroke and vascular dementia, named Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Recently, a mouse genetic model for CADASIL was developed, exhibiting the main features of the disease. Importantly this model established that cerebrovascular dysfunction is an early event that precedes white matter lesions (Joutel et al., JCI 2010). Here we report the effects of CADASIL on arterioles within the brain. Elevation of intravascular pressure to 20 mm Hg constricted isolated parenchymal arterioles (PAs) from WT and CADASIL brains to the same extent (34%). However, above 30 mm Hg, CADASIL PAs lost myogenic tone. At 40 mm Hg, PAs from WT and CADASIL constricted 39% and 25%, respectively, and the membrane potential of the CADASIL arterioles was 10 mV more hyperpolarized. Consistent with these finding, the current density of voltage‐dependent K+ channel currents was 30% greater in myocytes from CADASIL vs WT. These results indicate that the CADASIL mutation has a profound effect on PAs tone and point to a critical role for Kv channels. The present work provides new insights about the earliest events that initiate brain lesions in this model of cerebral ischemic small vessel disease. Supported by AHA 09POST2290090 (FD), the NIH HL095488, HL44455, HL58231 and the Totman Trust for Medical Research.