Abstract Introduction Ischaemic stroke is defined as a focal neurological deficit of vascular origin to the brain. During cerebral ischaemia, several cerebrovascular adaptations occur, including alterations in blood-brain barrier (BBB) permeability as well as recruitment of collateral arteri(ol)es, both determinant for stroke outcome. Understanding the molecular mechanisms that govern the function of BBB capillaries and collateral arteri(ol)es upon stroke is crucial to establish new effective therapies. Recently, our host lab has found that transcription factor Prdm16 in arterial endothelial cells (ECs) supports the functionalisation of collateral networks during hindlimb ischaemia. Here, we hypothesise that Prdm16 has a similar protective role during ischaemic stroke by preserving cerebrovascular function of both the collateral networks and the BBB. Methods To study the role of endothelial Prdm16 during ischaemic stroke, EC-specific Prdm16 knock-out mice were generated and were subjected to experimental stroke via permanent occlusion of the distal middle cerebral artery. The role of endothelial Prdm16 on both BBB and collateral function was studied at day 1 (i.e., the acute phase) and day 7 (i.e., the subacute phase) after stroke induction. BBB integrity was evaluated via immunohistochemistry and tracer dye leakage experiments. Collateral function was assessed using laser speckle contrast imaging and ultrafast ultrasound imaging. Results While many tissues feature an arterial-restricted vascular expression pattern for Prdm16, 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 protective role for Prdm16, we show that EC-specific Prdm16 loss worsened infarct growth in mice subjected to ischaemic stroke. Prdm16 loss in ECs resulted in decreased BBB integrity after stroke, as demonstrated by reduced levels of BBB junctional proteins and increased Evans blue extravasation and leakage of blood-borne IgG into the brain parenchyma. Additionally, EC-specific Prdm16 deficiency reduced cerebral collateral perfusion towards the ischaemic tissue and attenuated arteriolar vasoreactivity following ischaemic stroke. Conclusion Altogether, these data indicate a protective role for Prdm16 in preserving both arterial/arteriolar and capillary EC function following stroke. Although cerebral ischaemia induced a compensatory increase in Prdm16 in the cerebral vasculature, we show that Prdm16 levels are reduced in the aged brain vasculature. Since stroke is a disease of ageing, it could be speculated that reduced Prdm16 expression in aged animals primes the endothelium for dysfunction during stroke. Targeting Prdm16 may therefore be of great interest to ameliorate cerebrovascular function following ischaemic stroke, especially within the aged brain.
Kemps et al. (Fri,) studied this question.