Contribution of smooth muscle βENaC and Asic2 to pressure induced constriction in small renal and cerebral arteries

Pressure induced constriction (PIC), a mechanism of blood flow autoregulation, is mediated by vascular smooth muscle (VSM) cells. Independent studies show the beta subunit of the Epithelial Na+ Channel (bENaC) and the Acid Sensing Ion Channel 2 (Asic2) contribute to PIC in renal and cerebral vessels. Studies in the global bENaC hypomorph (bENaCm/m) and Asic2 knockout (Asic2-/-) models indicate that bENaC plays a dominant role in PIC responsiveness. PIC is abolished in renal and cerebral vessels from bENaCm/m mice yet attenuated ~50% in Asic2-/-. The PIC response has been proposed to protect downstream microvessels from barotrauma; loss of this function has been associated with multiple renal and cerebral pathologies including hypertension, stroke, and small vessel disease, leading to end organ injury in the kidneys and brain. However, whether loss of PIC alone, in absence of other pathologies, is sufficient to develop end organ injury in kidneys and brain is unknown. To address this question, we developed smooth muscle specific bENaC and Asic2 knockout mice by crossing SM22 Cre with bENaC and Asic2 floxed mice. Male and female Cre+/-/Asic2f/f or bENaCf/f and Cre-/-/Asic2f/f or bENaCf/f littermates were used for all studies. We measured systolic blood pressure from 6-24 weeks of age, assessed renal interlobar and middle cerebral artery PIC responses, and renal glomerular injury and brain water content in hippocampus, cerebellum, posterior/anterior cortex. Loss of SMC bENaC abolished PIC responsiveness in renal interlobar and middle cerebral arteries, leading to vascular injury assessed as glomerular injury and increased hippocampal water content (BBB disruption). Hypertension in this model is likely mediated by renal injury. Studies on renal and cerebral PIC responses from SMC Asic2-/- mice are underway, however, preliminary data indicate that renal PIC is suppressed but not abolished and we expect cerebral PIC will be similarly impacted. This model has a smaller increase in BP and no detectable change in hippocampal brain water content. Based on the partial retention of the renal PIC response, lack of disruption of the BBB, and lower systolic blood pressure in SMC Asic2-/-, we expect the little to no glomerular injury. Thus, while bENaC and Asic2 are expressed in renal and cerebral vascular SMCs, loss of bENaC has a greater impact on PIC responsiveness, and thus greater glomerular injury, brain water content, and rise in systolic blood pressure. Future studies are planned to determine if loss of the cerebral PIC response and BBB disruption promote cognitive dysfunction. Supported by NIH DK137167. 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.