DOI: 10.1161/str.55.suppl_1.tp33 ISSN: 0039-2499

Abstract TP33: Knockout of Kruppel-Like Factor 4 in Brain Endothelial Cells Accelerates Vascular and Neuronal Degeneration During Aging

Edwin Vázquez-Rosa, Matasha Dhar, Xudong Liao, Suwarna Chakraborty, Sunil J Tripathi, Hua Fang, Min-Kyoo Shin, Yeo Jung Koh, Emiko Miller, Xinmiao Tang, Preethy Sridharan, Kalyani Chaubey, Sarah Barker, Kathryn Franke, Coral Cintron-Perez, Roshan Padmanabhan, Hariprakash Haragopal, Margaret E Flanagan, Rajan Jain, Bradley D Winters, Brigid Wilson, Bindu Paul, Mukesh Jain, Andrew Pieper
  • Advanced and Specialized Nursing
  • Cardiology and Cardiovascular Medicine
  • Neurology (clinical)

As we get older, various aspects of our bodies start to decline, including brain function. The mechanisms behind the decline in brain function due to aging are still not well understood. The blood-brain barrier (BBB) is crucial for maintaining brain health and homeostasis by controlling both passive and active exchange of materials between the blood and brain. This barrier is predominantly composed of endothelial cells, which deteriorate in both aging and neurodegenerative disorders. Endothelial cells are also highly enriched in the Kruppel-like factor 4 (KLF4) transcription factor, which is reduced in expression as we age. In this study, we report that endothelial-specific KLF4 KO mice demonstrate accelerated brain aging, including accelerated BBB deterioration, neurodegeneration, and cognitive decline. Single-cell RNA sequencing from brain endothelial cells of endothelial-specific KLF4 KO mice demonstrate aberrantly high expression of adaptive and innate immune response genes, and live animal brain imaging across the lifespan reveals accelerated aging-related BBB deterioration, decreased blood flow, and impaired neurovascular coupling. Endothelial-specific KLF4 KO mice show increased neuroinflammation and neutrophil infiltration. Our data suggest that diminished endothelial cell KLF signaling with age could be a novel therapeutic target to preserve health and function of the aging brain.

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