Ischemic stroke is defined as focal neurological damage to the brain due to vascular insufficiency. During an ischemic event, several cerebrovascular adaptations occur, including alterations in blood-brain barrier (BBB) permeability as well as recruitment of collateral arteri(ol)es, which are both determinant for stroke outcome.
Understanding the molecular mechanisms that govern the maintenance and function of collateral arteri(ol)es and BBB capillaries upon cerebral ischemia is crucial to establish new effective therapies. Recently, our host lab found that transcription factor Prdm16 in arterial endothelial cells (ECs) supports arterial flow recovery during hind limb ischemia by maintaining their function. Here, we hypothesize that Prdm16 has a similar protective role during the progression of ischemic stroke by preserving cerebrovascular function. While many peripheral tissues feature an arterial-restricted Prdm16 expression pattern, we demonstrate that Prdm16 expression in the brain vasculature is not limited to arteri(ol)es, but is also present in BBB capillaries. In support of a maintenance role for Prdm16, we show that Prdm16 is upregulated within the brain vasculature in the perilesional region following cerebral ischemia. Furthermore, EC-specific Prdm16 loss results in increased infarct sizes in mice that were subjected to experimental stroke, suggesting a compensatory protective role for Prdm16 following ischemic stroke. In addition, EC-specific Prdm16 deficiency tends to decrease cerebral (collateral) blood flow and increase CD45+ immune cell infiltration within the ischemic lesion, indicating a potential role for Prdm16 in preserving both collateral arterial and BBB capillary EC function following ischemic stroke. Although cerebral ischemia induced a compensatory increase in Prdm16 in the cerebral vasculature, we show that Prdm16 levels are critically reduced in the aged brain vasculature. Since ischemic stroke is a disease of aging, it could be speculated that the reduced Prdm16 expression in aged animals primes the endothelium for dysfunction during ischemic stroke. Altogether, targeting Prdm16 and its downstream mediators may be of major interest to ameliorate cerebrovascular EC function following ischemic stroke, especially within the aged brain.