Endothelial KLF4: Crippling Vascular Injury?

T he health of the vascular endothelium is critical for normal vascular physiologic function, and dysfunction of the endothelium can lead to development of vascular disease, such as atherosclerosis and thrombosis. Endothelial cells (ECs) integrate hemodynamic and biochemical signals to regulate principal vascular functions, including vasoreactivity, permeability, immune cell homing, and thrombosis. Molecular, cellular, and genetic approaches over the past decade have strongly implicated members of the Kr€uppel-like factor (KLF) family of transcription factors as essential regulators of endothelial function in health and disease. Kr€uppel is the German word for “cripple,” a name given to the gap gene identified in Drosophila embryos whose absence results in abnormal segmentation and death. In this issue of Journal of American Heart Association, Yoshida and colleagues add important insights to this field and identify endothelial KLF4 as a negative regulator of neointimal formation in the biological response to vascular injury by counteracting the actions of nuclear factor kappa B (NF-jB), a central regulator of inflammation. The development of methods to culture ECs in the early 1970s was a major advance that ushered in the modern era of vascular biology research. Subsequent work from many laboratories has revealed that these cells can alter their phenotype in response to various physiologic and pathologic stimuli. For example, stimulation of the endothelium with proinflammatory cytokines produces a dysfunctional endothelium associated with elaboration of proadhesive and -thrombotic factors. Conversely, laminar flow induces an opposing gene profile associated with antithrombotic, -adhesive, and -inflammatory properties. Importantly, human arterial segments subject to laminar flow are less likely to develop atherogenic lesions, in contrast to “atheroprone” arterial branch points exposed to nonlaminar or disturbed flow. Emphasis on identifying central regulators integrating the effects of both hemodynamic and biochemical stimuli in the endothelium led to the discovery of the KLF family of transcription factors. Though several members of this family have been implicated in endothelial biology, the data are most compelling for KLF2 and KLF4. Initial links between KLFs and the endothelium were gleaned from the observations of Kuo and colleagues, who found that within embryonic vascular tissues, KLF2 was principally expressed in the endothelium. Subsequent work from several laboratories identified KLF2 and KLF4 as laminar flow-inducible transcription factors that broadly regulate endothelial gene products governing vasoreactivity, permeability, immune cell adhesion, and thrombosis. Furthermore, both factors were shown to inhibit endothelial proinflammatory targets by virtue of their ability to antagonize NF-jB. Whereas in vitro functional studies were highly supportive of the notion that KLF2 and KLF4 controlled basic endothelial functions, in vivo confirmation proved to be more difficult until recently. This gap in physiologic relevance was the result, in large part, of the challenges associated with the viability of KLF2 and KLF4 knockout (KO) mice. For example, global or endothelial-specific deletion of KLF2 results in death during embryonic development. Furthermore, global deletion of KLF4 results in death within hours of birth, thereby precluding studies in adult animals. However, endothelial-specific KLF4 KOs are viable. Using this mouse line and a second line overexpressing KLF4 in the endothelium, Zhou and colleagues showed recently that KLF4 confers an antiatherogenic and -thrombotic phenotype. Mechanistically, these effects were linked to the ability of KLF4 to inhibit NF-jB activity by affecting recruitment of critical coactivators to induce target genes, such as vascular cell adhesion molecule 1 (VCAM-1). Collectively, these observations provided the most cogent in vivo evidence to date implicating endothelial KLFs as essential regulators of vascular function in the adult animal. The current study by Yoshida and colleagues builds on the aforementioned work and evaluates the role of endothelial The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Department of Medicine, Harrington Heart & Vascular Institute, University Hospitals Case Medical Center and Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, OH. Correspondence to: Daniel I. Simon, MD, FAHA, Harrington Heart & Vascular Institute, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail: Daniel. [email protected] J Am Heart Assoc. 2014;3:e000769 doi: 10.1161/JAHA.113.000769. a 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.