Loss of pressure induced constriction responses in cerebral vessels promotes injury and inflammation in a mouse model of systemic lupus erythematosus 2310241

Abstract Introduction SLE is a chronic autoimmune disease in which up to 75% of patients develop neuropsychiatric symptoms (NPSLE), characterized by cognitive dysfunction, mood disorders and seizures; however, the pathogenesis of NPSLE is unclear. Pressure-induced constriction (PIC) is an intrinsic mechano-dependent response in small arteries in the brain. Because of the prevalent hypertension and vascular dysfunction in SLE, we hypothesized that SLE mice would have a loss of the PIC response as the disease progressed, leading to vascular injury, inflammation, and disruption of the blood brain barrier (BBB), all of which could contribute to the development of NPSLE. Methods Middle cerebral arteries were isolated from control (NZW) and SLE (NZBWF1) mice at 10 (pre disease) and 30 (advanced disease) weeks of age for assessment of PIC responses. In additional subsets of animals, cerebral vessels were isolated for flow cytometric analyses, cerebrovascular cytokine expression, and blood brain barrier integrity analysis. Results In SLE mice, PIC responses were attenuated 50% at 10 weeks of age and totally abolished by 30 weeks of age. In addition, SLE mice had increased expression of MCP-1, MCP-5, and CSF-1, and ICAM-1 in cerebral vessels compared to controls. We also found increased numbers of CD45+ leukocytes and CD11b+Ly6C+ monocytes in cerebral vessels of SLE mice. Finally, SLE mice also had a loss of BBB integrity, as indicated by increased Evans blue extravasation into brain tissue. Conclusion Taken together, these findings indicate progressive PIC impairment in SLE, leading to vascular inflammation and BBB disruption. Loss of the PIC response by 10 weeks of age precedes the onset of overt autoimmune disease, suggesting loss of PIC responses may be a causative factor in cardiovascular consequences in SLE. Future studies will examine mechanisms underlying loss of the PIC response in SLE cerebral vessels and protection against NPSLE symptoms. Funding Source R01 DK137167, P30 GM149404, U54 HL169191 Topic Categories Basic Autoimmunity (BA)