ArticleAmerican journal of physiology. Heart and circulatory physiology2018
Klf4 has an unexpected protective role in perivascular cells within the microvasculature.
Article in American journal of physiology. Heart and circulatory physiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Genome-wide association study of coronary flow reserve assessed by cardiac perfusion PET suggests a role for NF-κB pathway.Nature cardiovascular research · 2026Article
- Krüppel-like factor 4 transcription factor in blood-brain barrier endothelial cells: A potential role in Alzheimer's disease.Animal models and experimental medicine · 2025Review
- Mechanisms modulating foam cell formation in the arterial intima: exploring new therapeutic opportunities in atherosclerosis.Frontiers in cardiovascular medicine · 2024Review
- Clonal hematopoiesis with DNMT3A mutation is associated with lower white matter hyperintensity volume.CNS neuroscience & therapeutics · 2023Article
- Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.Arteriosclerosis, thrombosis, and vascular biology · 2022Article
- Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition.Matrix biology plus · 2021Article
- KLF4 (Kruppel-Like Factor 4)-Dependent Perivascular Plasticity Contributes to Adipose Tissue inflammation.Arteriosclerosis, thrombosis, and vascular biology · 2021Article
- Recent Discoveries on the Involvement of Krüppel-Like Factor 4 in the Most Common Cancer Types.International journal of molecular sciences · 2020Review
- Immune checkpoint inhibitor induces cardiac injury through polarizing macrophages via modulating microRNA-34a/Kruppel-like factor 4 signaling.Cell death & disease · 2020Article
- Pericyte Bridges in Homeostasis and Hyperglycemia.Diabetes · 2020Article
- Methods to label, image, and analyze the complex structural architectures of microvascular networks.Microcirculation (New York, N.Y. : 1994) · 2019Review
- Perivascular cell-specific knockout of the stem cell pluripotency gene Oct4 inhibits angiogenesis.Nature communications · 2019Article
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
Recent smooth muscle cell (SMC) lineage-tracing studies have revealed that SMCs undergo remarkable changes in phenotype during development of atherosclerosis. Of major interest, we demonstrated that Kruppel-like factor 4 (KLF4) in SMCs is detrimental for overall lesion pathogenesis, in that SMC-specific conditional knockout of the KLF4 gene ( Klf4) resulted in smaller, more-stable lesions that exhibited marked reductions in the numbers of SMC-derived macrophage- and mesenchymal stem cell-like cells. However, since the clinical consequences of atherosclerosis typically occur well after our reproductive years, we sought to identify beneficial KLF4-dependent SMC functions that were likely to be evolutionarily conserved. We tested the hypothesis that KLF4-dependent SMC transitions play an important role in the tissue injury-repair process. Using SMC-specific lineage-tracing mice positive and negative for simultaneous SMC-specific conditional knockout of Klf4, we demonstrate that SMCs in the remodeling heart after ischemia-reperfusion injury (IRI) express KLF4 and transition to a KLF4-dependent macrophage-like state and a KLF4-independent myofibroblast-like state. Moreover, heart failure after IRI was exacerbated in SMC Klf4 knockout mice. Surprisingly, we observed a significant cardiac dilation in SMC Klf4 knockout mice before IRI as well as a reduction in peripheral resistance. KLF4 chromatin immunoprecipitation-sequencing analysis on mesenteric vascular beds identified potential baseline SMC KLF4 target genes in numerous pathways, including PDGF and FGF. Moreover, microvascular tissue beds in SMC Klf4 knockout mice had gaps in lineage-traced SMC coverage along the resistance arteries and exhibited increased permeability. Together, these results provide novel evidence that Klf4 has a critical maintenance role within microvascular SMCs: it is required for normal SMC function and coverage of resistance arteries. NEW & NOTEWORTHY We report novel evidence that the Kruppel-like factor 4 gene ( Klf4) has a critical maintenance role within microvascular smooth muscle cells (SMCs). SMC-specific Klf4 knockout at baseline resulted in a loss of lineage-traced SMC coverage of resistance arteries, dilation of resistance arteries, increased blood flow, and cardiac dilation.
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Registered trials
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