Flow Perturbation Is Linked to Endothelial PAR Signaling

Abstract

The vascular endothelium integrates a variety of humoral stimuli and biophysical forces to maintain patent microvascular and macrovacular beds. At the interface between the blood and vessel wall, endothelial cells communicate in both directions by the release of growth factors, cytokines, and bioactive mediators to maintain vascular homeostasis. Endothelial dysfunction is central for acute systemic inflammatory syndromes including sepsis and chronic inflammatory disorders such as atherosclerosis. Early atherosclerotic lesions preferentially develop at sites where laminar flow patterns are disturbed, and endothelial cells sense changes in biomechanical forces that result from flow perturbation. Exposure to shear forces rapidly activates G proteins, ion fluxes, and mechanosensing receptors, including integrins and a complex involving PECAM-1, VEGFR-2, and vascular endothelial cell cadherin.1 Activation of downstream signaling pathways results in cytoskeletal reorganization and a flow-adapted endothelial phenotype.2 Endothelial cells under laminar flow have an atheroprotected phenotype, but perturbation of laminar flow patterns induces a complex transcriptional response that favors the induction of adhesion molecules, proinflammatory cytokines, and procoagulant genes. See page 1185 Dekker et al profiled the repertoire of laminar flow-regulated genes in endothelial cells and identified lung Krueppel-like factor (LKLF or KLF-2) that was selectively induced on flow adaptation and suppressed by the inflammatory mediator tumor necrosis factor (TNF)α.3 KLF2 was indeed tonically expressed in vivo in noninflamed large vessel endothelial cells. KLFs are zinc finger transcription factors similar to Sp1 and Egr-1 families that act as transcriptional repressors or activators by high affinity binding to a CACCC promoter/enhancer element. KLF2 was originally identified …