The transition to a dysfunction endothelial cell phenotype is regulated by multiple environmental factors, including both systemic risk factors (ex. oxidized LDL) and local blood flow patterns. My research suggests that local matrix composition is a novel regulator of endothelial cell dysfunction. Transitional matrix proteins (ex. fibronectin) accumulate in the subendothelial matrix early during atherogenesis and prime endothelial cells for dysfunction by enhancing flow-induced permeability and proinflammatory gene expression. In contrast, basement membrane proteins limit endothelial cell dysfunction. Multiple atherogenic stimuli, including disturbed flow and oxidized LDL, activate the Rac/cdc42 effector p21 activated kinase (PAK), and PAK inhibitors reduce endothelial permeability and proinflammatory responses both in vitro and at atherosclerosis- prone sites in vivo. Despite activation of upstream pathways, basement membrane proteins do not support PAK activation, suggesting that signals from the basement membrane inhibit PAK to limit endothelial cell dysfunction. As such, PAK activation in vivo is restricted to regions of transitional matrix deposition. Protein kinase A (PKA) phosphorylates and inhibits PAK in cells in suspension. In addition, PKA reduces both proinflammatory gene expression and endothelial permeability, suggesting PKA is a good candidate for matrix- specific PAK suppression. Preliminary data show that basement membrane proteins enhance flow-induced PKA activation, and inhibiting PKA in cells on basement membrane proteins is sufficient to restore flow- induced PAK activation and proinflammatory responses. These data lead us to hypothesize that basement membrane proteins utilize a PKA-dependent signal to inhibit PAK and limit endothelial cell dysfunction, whereas transitional matrix deposition primes endothelial cells to progress to a dysfunctional phenotype. The proposed work will test this hypothesis by determining the mechanisms by which matrix signaling modulates PKA activation (Aim 1) and by exploring the molecular mechanisms of PKA-dependent PAK inhibition (Aim 2). To illustrate the broad scope of this novel signaling axis across multiple atherogenic signals, we will determine how matrix composition and signaling through the PKA and PAK pathways affect oxidized LDL-induced endothelial cell dysfunction (Aim 3). This work will utilize a multifactorial approach to provide insight into the role of the endogenous basement membrane as a novel atheroprotective agent.

Public Health Relevance

Atherosclerosis, a chronic inflammatory disease of the vessel wall, is the leading cause of death in developed countries. Our research suggests that changes in the local extracellular matrix may serve as a form of tissue memory. Normal components of the tissue matrix limit cellular responsiveness to transient injurious stimuli, while transitional matrix deposition in response to chronic stimuli enhances cellular responsiveness to propagate tissue remodeling. Understanding the molecular mechanisms by which matrix composition affects cell physiology could provide novel therapeutic targets to limit chronic inflammatory diseases, such as atherosclerosis and arthritis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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Goldberg, Suzanne H
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Louisiana State University Hsc Shreveport
Schools of Medicine
United States
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Yurdagul Jr, Arif; Sulzmaier, Florian J; Chen, Xiao L et al. (2016) Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression. J Cell Sci 129:1580-91
Yurdagul Jr, Arif; Orr, A Wayne (2016) Blood Brothers: Hemodynamics and Cell-Matrix Interactions in Endothelial Function. Antioxid Redox Signal 25:415-34
Navratil, Aaron R; Vozenilek, Aimee E; Cardelli, James A et al. (2015) Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses. Atherosclerosis 242:424-32
Becker, Felix; Potepalov, Sergey; Shehzahdi, Romana et al. (2015) Downregulation of FoxC2 Increased Susceptibility to Experimental Colitis: Influence of Lymphatic Drainage Function? Inflamm Bowel Dis 21:1282-96
Holloway, Paul M; Durrenberger, Pascal F; Trutschl, Marjan et al. (2015) Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion-Induced Neutrophil Recruitment. Arterioscler Thromb Vasc Biol 35:1936-44
Chen, Jie; Green, Jonette; Yurdagul Jr, Arif et al. (2015) αvβ3 Integrins Mediate Flow-Induced NF-κB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation. Am J Pathol 185:2575-89
Singh, Nikhlesh K; Kotla, Sivareddy; Dyukova, Elena et al. (2015) Disruption of p21-activated kinase 1 gene diminishes atherosclerosis in apolipoprotein E-deficient mice. Nat Commun 6:7450
Chen, Jie; Leskov, Igor L; Yurdagul Jr, Arif et al. (2015) Recruitment of the adaptor protein Nck to PECAM-1 couples oxidative stress to canonical NF-κB signaling and inflammation. Sci Signal 8:ra20
Yurdagul Jr, Arif; Green, Jonette; Albert, Patrick et al. (2014) α5β1 integrin signaling mediates oxidized low-density lipoprotein-induced inflammation and early atherosclerosis. Arterioscler Thromb Vasc Biol 34:1362-73
Yurdagul Jr, Arif; Kleinedler, James J; McInnis, Marshall C et al. (2014) Resveratrol promotes endothelial cell wound healing under laminar shear stress through an estrogen receptor-α-dependent pathway. Am J Physiol Heart Circ Physiol 306:H797-806

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