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Endothelial FN (Fibronectin) Deposition by ?5?1 Integrins Drives Atherogenic Inflammation.

ABSTRACT: Objective- Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to an FN (fibronectin)-rich matrix preceding lesion development. Endothelial cell interactions with FN prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic FN accumulation remain unknown. We previously demonstrated that oxLDL (oxidized low-density lipoprotein) promotes endothelial proinflammatory gene expression by activating the integrin ?5?1, a classic mediator of FN fibrillogenesis. Approach and Results- We now show that oxLDL drives robust endothelial FN deposition and inhibiting ?5?1 (blocking antibodies, ?5 knockout cells) completely inhibits oxLDL-induced FN deposition. Consistent with this, inducible endothelial-specific ?5 integrin deletion in ApoE knockout mice significantly reduces atherosclerotic plaque formation, associated with reduced early atherogenic inflammation. Unlike TGF? (transforming growth factor ?)-induced FN deposition, oxLDL does not induce FN expression (mRNA, protein) or the endothelial-to-mesenchymal transition phenotype. In addition, we show that cell-derived and plasma-derived FN differentially affect endothelial function, with only cell-derived FN capable of supporting oxLDL-induced VCAM-1 (vascular cell adhesion molecule 1) expression, despite plasma FN deposition by oxLDL. The inclusion of alternative exon EIIIA (EDA) of FN (EIIIA) and alternative exon EIIIB (EDB) of FN (EIIIB) domains in cell-derived FN mediates this effect, as EIIIA/EIIIB knockout endothelial cells show diminished oxLDL-induced inflammation. Furthermore, our data suggest that EIIIA/EIIIB-positive cellular FN is required for maximal ?5?1 recruitment to focal adhesions and FN fibrillogenesis. Conclusions- Taken together, our data demonstrate that endothelial ?5 integrins drive oxLDL-induced FN deposition and early atherogenic inflammation. Additionally, we show that ?5?1-dependent endothelial FN deposition mediates oxLDL-dependent endothelial inflammation and FN fibrillogenesis.

SUBMITTER: Al-Yafeai Z

PROVIDER: S-EPMC6209122 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Endothelial FN (Fibronectin) Deposition by α5β1 Integrins Drives Atherogenic Inflammation.

Al-Yafeai Zaki Z Yurdagul Arif A Peretik Jonette M JM Alfaidi Mabruka M Murphy Patrick A PA Orr A Wayne AW

Arteriosclerosis, thrombosis, and vascular biology 20181101 11

Objective- Alterations in extracellular matrix quantity and composition contribute to atherosclerosis, with remodeling of the subendothelial basement membrane to an FN (fibronectin)-rich matrix preceding lesion development. Endothelial cell interactions with FN prime inflammatory responses to a variety of atherogenic stimuli; however, the mechanisms regulating early atherogenic FN accumulation remain unknown. We previously demonstrated that oxLDL (oxidized low-density lipoprotein) promotes endot ...[more]

PMID: 30354234

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Project description:Background and Purpose- Cellular Fn-EDA (fibronectin containing extra domain A) is expressed in activated endothelial cells and elevated in circulation in patients with cardiovascular diseases. Although global deficiency of Fn-EDA in mice improves stroke outcome, the specific contribution of plasma versus endothelium Fn-EDA in stroke outcome is currently unknown. We investigated the role of plasma versus endothelial Fn-EDA in stroke exacerbation in the comorbid condition of hyperlipidemia. Methods- We generated novel plasma Fn-EDA-/- ( Fn-EDA fl/fl Alb Cre) and endothelial Fn-EDA-/- ( Fn-EDA fl/fl Tie2 Cre) strains on hyperlipidemic apolipoprotein E-deficient ( ApoE-/-) background. By following the Stroke Therapy Academic Industry Roundtable guidelines, we evaluated stroke outcome in male and female mice. Susceptibility to ischemia/reperfusion injury was evaluated in 2 different models of stroke: intraluminal monofilament and embolic model on days 1, 3, and 7. Quantitative assessment of stroke outcome was evaluated by measuring infarct volume (by magnetic resonance imaging), cerebral blood flow (by laser speckle imaging), neurological and sensory-motor outcome, and postischemic thrombo-inflammation (platelet thrombi, fibrin, neutrophil, phospho-NFκB [nuclear factor κB], TNFα [tumor necrosis factor α], and IL1β [interleukin 1β]). Results- Stroke outcome was comparable in ApoE-/- Fn-EDA fl/fl Tie2 Cre and control ApoE-/- Fn-EDA fl/fl mice suggesting endothelial Fn-EDA does not contribute to stroke. ApoE-/- Fn-EDA fl/fl Alb Cre mice exhibited significantly smaller infarcts and improved neurological and sensory-motor outcome at days 1, 3, and 7 in monofilament and embolic models of stroke. Improved stroke outcome was concomitant with enhanced survival, and decreased postischemic thrombo-inflammatory response ( P<0.05 versus ApoE-/- Fn-EDA fl/fl). No sex-based differences were observed. Laser speckle imaging revealed significantly improved regional cerebral blood flow at 1 hour in ApoE-/- Fn-EDA fl/fl Alb Cre mice suggesting plasma Fn-EDA promotes postischemic secondary thrombosis. Coinfusion of anti-Fn-EDA antibody with r-tPA (recombinant tissue-type plasminogen activator) in ApoE-/- mice, 1 hour after embolization, improved stroke outcome with enhanced survival, and improved neurological outcome ( P<0.05 versus r-tPA). Conclusions- Genetic evidence suggests that plasma Fn-EDA exacerbates stroke outcome by promoting postischemic thrombo-inflammation. Interventions targeting plasma Fn-EDA may reduce brain damage after reperfusion.

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Endothelial FN (Fibronectin) Deposition by ?5?1 Integrins Drives Atherogenic Inflammation.

Publications

Endothelial FN (Fibronectin) Deposition by α5β1 Integrins Drives Atherogenic Inflammation.

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