Endothelial KLF4 depletion drives age-related neurovascular dysfunction and neuropsychiatric impairment

• 成果类型: Article
• 署名作者: Dhar, Matasha; Vazquez-Rosa, Edwin; Chaubey, Kalyani; Miller, Emiko; Corella, Sofia G.; Chakraborty, Suwarna; Tripathi, Sunil Jamuna; Das, Tapatee; Liao, Xudong; Alosman, Mohamed Alkassem; Fang, Hua; Koh, Yeojung; Sridharan, Preethy S.; Franke, Kathryn; Cintron-Perez, Coral J.; Cintron-Perez, Adrian A.; Tomco, Taylor; Indrakumar, Vidya; Rubin, Phoebe J.; Pieper, Justin G.; Ashiku, Luke A.; Shin, Min-Kyoo; Tang, Xinmiao; Padmanabhan, Roshan; Haragopal, Hariprakash; Flanagan, Margaret E.; Jain, Rajan; Winters, Bradley D.; Wilson, Brigid M.; Paul, Bindu D.; Jain, Mukesh K.; Pieper, Andrew A.
• 署名单位: University System of Ohio; Case Western Reserve University; University Hospitals of Cleveland; University System of Ohio; US Department of Veterans Affairs; Case Western Reserve University; Veterans Health Administration (VHA); Louis Stokes Cleveland Veterans Affairs Medical Center; University System of Ohio; Case Western Reserve University; University System of Ohio; Case Western Reserve University; Johns Hopkins University; Brown University; Massachusetts Institute of Technology (MIT); University System of Ohio; Case Western Reserve University; University of California System; University of California Santa Barbara; Northeastern University; Seoul National University (SNU); Seoul National University (SNU); Shanghai University of Traditional Chinese Medicine; University System of Ohio; Northeast Ohio Medical University (NEOMED); University of Texas System; University of Texas at San Antonio; University of Texas System; University of Texas at San Antonio; Northwestern University; Feinberg School of Medicine; University of Pennsylvania; University System of Ohio; Case Western Reserve University; Johns Hopkins University; Johns Hopkins Medicine; Johns Hopkins University; Johns Hopkins Medicine; Brown University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2426990123
• 发表日期: 2026-06-23
• 页码: e2426990123
• 关键词: blood-brain barrier; Aging; neurodegeneration; KLF4; endothelial cell; blood-brain-barrier; nitric-oxide; microglial activation; cognitive impairment; PROTEIN OXIDATION; rat-brain; cells; memory; transcriptome; antioxidants

摘要

Deterioration of the blood-brain barrier (BBB), including impaired neurovascular uncoupling, contributes to cognitive decline in aging. The BBB is formed principally by brain microvascular endothelial cells (ECs), and ECs throughout the body are enriched for the transcription factor Kr & uuml;ppel-like factor 4 (KLF4). Because KLF4 levels in ECs decrease with age, we tested whether that decline contributes to aging-related BBB deterioration, neurovascular dysfunction, and cognitive impairment. Using EC-specific Klf4 knockout mice (EC-K4KO), we show that loss of EC KLF4 accelerates multiple age-related brain pathologies. Indeed, middle-aged EC-K4KO mice display pathological features that are not normally observed until advanced age, including marked BBB leakage, impaired neurovascular coupling, loss of microvessels, increased oxidative damage, neuroinflammation, neurodegeneration, anxiety-like behavior, and cognitive deficits. Single-cell RNA sequencing of brain vasculature reveals dysregulation of immune response and barrier-related genes in ECs lacking KLF4, indicating that KLF4 maintains brain endothelial homeostasis by constraining proinflammatory and senescence programs at the chromatin level. Together, these results identify loss of EC KLF4 as a key driver of neurovascular decline and age-associated cognitive dysfunction.