Evaluation of the impact of genetic depletion of CD8 + lymphocytes on neurovascular integrity in the TAC-induced hypertension mouse model

Abstract Introduction Arterial hypertension alters the central nervous system's structural and functional integrity, leading to the decline of cognitive functions. Experimentally, the murine model of cerebral hypertension induced by aortic coarctation (TAC) allows us to investigate the brain damage caused by hypertension and subsequent cognitive decline. Novel studies conducted in our laboratory have identified a brain parenchyma infiltration of CD8+ lymphocytes releasing interferon-gamma (IFN-γ) as one of the crucial mechanisms of cerebral injury defined by the decline of cognitive functions as well as a marked cortical hypoperfusion associated with a loss of pericytes at the capillary level. Aim Since CD8 + lymphocytes are not the only immune cells able to produce IFN-γ, we generated a mouse model genetically defective for CD8 and subjected them to transverse aortic constrictin (TAC) to assess whether the observed phenotype is exclusively due to lymphocytes action. Methods We subjected CD8 knock-out (KO) mice and relative WT controls TAC and determined brain damage via advanced magnetic resonance imaging (MRI) after 4 weeks, evaluating perfusion, brain volumes, and white matter microstructure integrity. Cognitive functions were evaluated after MRI imagingby Morris Water Maze (MWM) test. Pericytes coverage was assessed at 4 weeks executing a DAPI - CD31 - PDGFRβ immunostaining. Results Advanced MRI analyses indicated that CD8 KO mice are protected from the reduction of cortical perfusion induced by TAC in control WT mice (p = 0.0002) remaining comparable to the control sham mice (Fig. A). Brain volumes and microstructural integrity of white matter are free from significant alterations. The MWM test highlights a rescue of cognitive performance in CD8 KO mice subjected to TAC if compared to control WT mice while remaining comparable to the control sham mice (Fig. B). Immunohistochemical assessments support that CD8 KO mice are not protected from pericytes loss at the capillary level regardless of a pressure overload challenge (Fig. C). Conclusions The increased cortical blood perfusion associated with a rescue of cognitive performance in CD8 KO mice subjected to a hypertensive stimulus highlights the critical involvement of CD8+ lymphocytes in the pathogenesis of hypertension-induced cognitive decline. Unexpectedly, CD8+ lymphocytes seem to play a pivotal role in cerebral microvasculature regulating the endothelium - pericyte cross-talk irrespective of a hypertensive challenge.