"Go with the flow": how Krüppel-like factor 2 regulates the vasoprotective effects of shear stress

Abstract

Laminar shear stress is known to confer potent anti-inflammatory, antithrombotic, and antiadhesive effects by differentially regulating endothelial gene expression. The identification of Krüppel-like factor 2 as a flow-responsive molecule has greatly advanced our understanding of molecular mechanisms governing vascular homeostasis. This review summarizes the current understanding of Krüppel-like factor 2 action in endothelial gene expression and function.

FIG. 1.

Flow-dependent regulation of KLF2. Whole-mount in situ hybridization of WT or sih mutant zebrafish embryos at 48 h, probed for Flk (VEGFR2) or KLF2a. Insets show close-ups of the trunk vasculature. Anal sphincter staining is indicated by arrowheads. Reprinted with permission from Parmar et al. (70). Flk, fetal liver kinase; KLF2, Krüppel-like factor 2; sih, silent heart; VEGFR2, vascular endothelial growth factor receptor 2; WT, wild type. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

Endothelial-specific expression of LKLF and claudin-5 in the normal human aorta. (A) Overview of a section of the thoracic aorta of a 13-year-old female stained with nuclear fast red. Nonradioactive mRNA in situ hybridizations was performed on consecutive sections, using antisense riboprobes of LKLF (B, D, E), claudin-5 (H), cytochrome P450 1B1 (I), and the endothelial-specific marker von Willebrand factor (C, F, G). The detection of the mRNA–probe hybrid results in a blue color associated with the nuclei. Panels (E) and (G) show no significant expression of the LKLF mRNA (E), whereas von Willebrand factor (G) is consistently and specifically expressed in the endothelium of the entire specimen. Stacks of nuclei are visible because of the thickness of the sections (16 μm) and the conical shape of the branching artery. Claudin-5 was specifically expressed in the endothelium (H), but detection of the cytochrome P450 1B1 mRNA was too close to background hybridization levels (I). Reprinted with permission from Dekker et al. (26). LKLF, lung Krüppel-like factor. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 3.

Schematic diagram of the functions of KLF2. CNP, C-natriuretic peptide; ET-1, endothelin-1; ASS, arginosuccinate synthase; AM, adrenomedullin; ACE, angiotensin converting enzyme; TM, thrombomodulin; APC, activated protein C; PAI-1, plasminogen activator inhibitor-1; eNOS, endothelial nitric oxide synthase; PAR-1, protease-activated receptor 1; TF, tissue factor; CD40L, CD40 ligand; MMP, matrix metalloproteinase; MCP-1, monocyte chemotactic protein 1; IL-6/8, interleukin 6/8; CD62L, CD62 ligand; S1P, sphingosine-1 phosphate; IL-4, interleukin-4; Nrf2, nuclear factor erythroid 2-like; NQO1, NAD(P)H:quinine oxidoreductase-1; HO-1, heme oxygenease-1; MAPK, mitogen-activated protein kinase; P-actin BP, phosphorylated actin-binding protein; VCAM, vascular cell adhesion molecule; ATF2, activating transcription factor 2; AP-1, activator protein 1; SMAD, Sma and Mad related protein; Ang, angiopoetin; SEMA3F, semaphorin 3F; HIF-1α, hypoxia-inducible factor 1 alpha. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

KLF2 heterozygous mice develop more atherosclerosis. Male littermate KLF2^+/+/ApoE^–/– and KLF2^+/–/ApoE^–/– mice at 6 weeks of age were fed a high-fat, high-cholesterol diet for 20 weeks. Aortas were harvested and Sudan IV–stained for lipid. Two representative pairs of fixed and stained aortas en face. K2^+/– indicates KLF2^+/–. Reprinted with permission from Atkins et al. (6). (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 5.

KLF2 inhibits VEGF-A-mediated angiogenesis. Photographs of nude mouse ears before [(–)VEGF] and after [(+)VEGF] treatment with VEGF-A in the presence (Ad-K2) and absence (Ad-GFP) of adenoviral KLF2. Reprinted with permission from Bhattacharya et al. (9). (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 6.

Schematic diagram showing upstream regulation of KLF2 in endothelial cells. PI3K, phosphoinositide-3 kinase; MEF2, myocyte enhancer factor 2; PCAF, P 300/CBP-associated factor; HDAC4/5, histone deacetylase 4/5; Rho pathway, Ras homolog pathway; hnRNP-D, heterogeneous nuclear ribonucleoprotein D; ERK, extracellular signal-regulated kinase; TNFα, tumor necrosis factor alpha; IL-1β, interleukin 1 beta. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).