| Autor: |
Sweet DR; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH.; Department of Pathology Case Western Reserve University Cleveland OH., Padmanabhan R; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH., Liao X; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH., Dashora HR; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH., Tang X; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH., Nayak L; Division of Hematology and Oncology University Hospitals Cleveland Medical Center Cleveland OH., Jain R; Department of Cell and Developmental Biology, Perelman School of Medicine University of Pennsylvania Philadelphia PA., De Val S; Department of Physiology, Anatomy and Genetics University of Oxford UK., Vinayachandran V; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH., Jain MK; Case Cardiovascular Research Institute, Case Western Reserve University, and Harrington Heart and Vascular Institute University Hospitals Cleveland Medical Center Cleveland OH.; Division of Biology and Medicine Warren Alpert Medical School of Brown University Providence RI. |
| Abstrakt: |
Background Proper function of endothelial cells is critical for vascular integrity and organismal survival. Studies over the past 2 decades have identified 2 members of the KLF (Krüppel-like factor) family of proteins, KLF2 and KLF4, as nodal regulators of endothelial function. Strikingly, inducible postnatal deletion of both KLF2 and KLF4 resulted in widespread vascular leak, coagulopathy, and rapid death. Importantly, while transcriptomic studies revealed profound alterations in gene expression, the molecular mechanisms underlying these changes remain poorly understood. Here, we seek to determine mechanisms of KLF2 and KLF4 transcriptional control in multiple vascular beds to further understand their roles as critical endothelial regulators. Methods and Results We integrate chromatin occupancy and transcription studies from multiple transgenic mouse models to demonstrate that KLF2 and KLF4 have overlapping yet distinct binding patterns and transcriptional targets in heart and lung endothelium. Mechanistically, KLFs use open chromatin regions in promoters and enhancers and bind in context-specific patterns that govern transcription in microvasculature. Importantly, this occurs during homeostasis in vivo without additional exogenous stimuli. Conclusions Together, this work provides mechanistic insight behind the well-described transcriptional and functional heterogeneity seen in vascular populations, while also establishing tools into exploring microvascular endothelial dynamics in vivo. |
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