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Atherosclerosis is a chronic inflammatory disease of arteries that develops preferentially at branches and bends that are exposed to disturbed blood flow. Vascular function is modified by flow, in part, via the generation of mechanical forces that alter multiple physiological processes in endothelial cells. Shear stress has profound effects on vascular inflammation; high uniform shear stress prevents leukocyte recruitment to the vascular wall by reducing endothelial expression of adhesion molecules and other inflammatory proteins, whereas low oscillatory shear stress has the opposite effects. Here, we review the molecular mechanisms that underpin the effects of shear stress on endothelial inflammatory responses. They include shear stress regulation of inflammatory mitogen-activated protein kinase and nuclear factor-κB signaling. High shear suppresses these pathways through the induction of several negative regulators of inflammation, whereas low shear promotes inflammatory signaling. Furthermore, we summarize recent studies indicating that inflammatory signaling is highly sensitive to pulse wave frequencies, magnitude, and direction of flow. Finally, the importance of systems biology approaches (including omics studies and functional screening) to identify novel mechanosensitive pathways is discussed., (© 2014 American Heart Association, Inc.)

Background: Ischemic stroke is a main cause of mortality. Blood-brain barrier (BBB) breakdown appears to play a critical role in inflammation in patients with ischemic stroke and acceleration of brain injury. The BBB has a protective function and is composed of endothelial cells, pericytes, and astrocytes. In ischemic stroke treatments, regulation of vascular endothelial growth factor (VEGF)-A and vascular endothelial growth factor receptor (VEGFR)-2 is a crucial target despite adverse effects. Our previous study found that loss of C-type lectin family 14 member A (CLEC14A) activated VEGF-A/VEGFR-2 signaling in developmental and tumoral angiogenesis. Here, we evaluate the effects of BBB impairment caused by CLEC14A deficiency in ischemia-reperfusion injury.Methods: In vitro fluorescein isothiocyanate (FITC)-dextran permeability, transendothelial electrical resistance (TEER) assay, and immunostaining were used to evaluate endothelial integrity. BBB permeability was assessed using Evans blue dye and FITC-dextran injection in Clec14a-/- (CLEC14A-KO) mice and wild-type mice. Middle cerebral artery occlusion surgery and behavioral assessments were performed to evaluate the neurologic damage. The change of tight junctional proteins, adhesion molecules, pro-inflammatory cytokines, and microglial were confirmed by immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction of brain samples.Results: In endothelial cells, knockdown of CLEC14A increased FITC-dextran permeability and decreased transendothelial electrical resistance; the severity of this effect increased with VEGF treatment. Immunofluorescence staining revealed that tight junctional proteins were attenuated in the CLEC14A knockdown endothelial cells. Consistent with the in vitro results, CLEC14A-KO mice that were injected with Evans blue dye had cerebral vascular leakage at postnatal day 8; wild-type mice had no leakage. We used a middle cerebral artery occlusion model and found that CLEC14A-KO mice had severe infarcted brain and neurological deficits with upregulated VEGFR-2 expression. FITC-dextran leakage was present in CLEC14A-KO mice after ischemia-reperfusion, and the numbers of tight junctional molecules were significantly decreased. Loss of CLEC14A increased the pro-inflammatory response through adhesion molecule expression, and glial cells were activated.Conclusions: These results suggest that activation of VEGFR-2 in CLEC14A-KO mice aggravates ischemic stroke by exacerbating cerebral vascular leakage and increasing neuronal inflammation after ischemia-reperfusion injury. [ABSTRACT FROM AUTHOR]