Increased luminal pressure in brain capillaries drives TRPC3-dependent depolarization and constriction of...

Cerebral autoregulation ensures constant blood flow, an essential condition of brain health. A fundamental parameter of the brain circulation is the dynamic regulation of microvessel diameter to allow for adjustments in resistance to blood pressure changes. Pericytes are a family of mural cells that wrap around the capillary endothelium and contribute to the dynamic control of capillary diameter. We sought to determine whether and how brain pericytes constrict in response to blood pressure elevation with in vivo two-photon microscopy, electrophysiology, and ex vivo arteriolar-capillary myography of mice with conditional mural cell knockout or with expression of a genetically encoded Ca²⁺ indicator. In first- to fourth-order capillaries, pericytes displayed a rapid and measurable response to pressure by decreasing luminal diameter, depolarizing membrane potentials, and increasing cytoplasmic Ca²⁺ signaling. Pharmacological and imaging approaches revealed that transient receptor potential channel 3 (TRPC3) and voltage-gated Ca²⁺ channels were sequentially activated to promote fast constriction. Genetic ablation of TRPC3 resulted in decreased currents, loss of membrane depolarization, and near-complete ablation of the generation of tone over a standard pressure curve in transitional pericytes but not in upstream arterioles. Together, our findings identify TRPC3 channel activation as critical for proximal pericyte depolarization and contraction in response to pressure, highlighting the signaling differences between arteriolar and capillary blood flow regulation.