Impaired dynamics of brain precapillary sphincters and pericytes at first order capillaries explains reduced neurovascular functions in aging

ABSTRACT The microvascular inflow tract (MIT), comprising the penetrating arterioles, precapillary sphincters, and first order capillaries, is the bottleneck for brain blood flow and energy supply. However, the exact structural and functional alterations of the MIT during aging remain elusive. In vivo 4-dimensional two-photon imaging showed an age-dependent decrease in vaso-responsivity, with reduced sensitivity of the MIT to pinacidil and papaverine, vasoconstrictor endothelin-1, and nitric oxide synthase inhibitor L-NAME. This was accompanied by an age-dependent decrease in capillary density close to the arterioles and loss of pericyte processes, though the number of pericyte somas and pericyte αSMA density were preserved. The age-related reduction in vascular reactivity was most pronounced at precapillary sphincters, highlighting their crucial role in capillary blood flow regulation. Mathematical modeling revealed dysregulated but preserved pressure and flow in aged mice during vasoconstriction. Preventing reduced responsivity of the MIT may ameliorate the blood flow decrease associated with aging-related brain frailty.