Flow signaling and atherosclerosis

Abstract

Atherosclerosis rarely develops in the region of arteries exposed to undisturbed flow (u-flow, unidirectional flow). Instead, atherogenesis occurs in the area exposed to disturbed flow (d-flow, multidirectional flow). Based on these general pathohistological observations, u-flow is considered to be atheroprotective, while d-flow is atherogenic. The fact that u-flow and d-flow induce such clearly different biological responses in the wall of large arteries indicates that these two types of flow activate each distinct intracellular signaling cascade in vascular endothelial cells (ECs), which are directly exposed to blood flow. The ability of ECs to differentially respond to the two types of flow provides an opportunity to identify molecular events that lead to endothelial dysfunction and atherosclerosis. In this review, we will focus on various molecular events, which are differentially regulated by these two flow types. We will discuss how various kinases, ER stress, inflammasome, SUMOylation, and DNA methylation play roles in the differential flow response, endothelial dysfunction, and atherosclerosis. We will also discuss the interplay among the molecular events and how they coordinately regulate flow-dependent signaling and cellular responses. It is hoped that clear understanding of the way how the two flow types beget each unique phenotype in ECs will lead us to possible points of intervention against endothelial dysfunction and cardiovascular diseases.

Ponatinib Activates an Inflammatory Response in Endothelial Cells via ERK5 SUMOylation

“…Endothelial ERK5 can be phosphorylated at multiple sites, each of which confers different biological functions ( 51 , 52 , 68 – 70 ). Among them, ERK5 S496 phosphorylation plays a crucial role in EC inflammation.…”

MAGI1 as a link between endothelial activation and ER stress drives atherosclerosis

“…First, to determine the role of MAGI1 in regulation of EC activation, we isolated mouse lung ECs (MLECs) from NLC and Magi1 -/animals and exposed them to 2 inflammatory conditions: stimulation by TNF-α and overexpression of p90RSK. These conditions are known to activate NF-κB, a prototypical proinflammatory molecule, and to increase VCAM-1 expression in ECs (2,21). Treatment with TNF-α increased VCAM-1 expression in NLC MLECs but not in Magi1 -/-MLECs ( Figure 1A, top, and Figure 1B).…”

“…Proatherogenic agonists, such as inflammatory cytokines and growth factors as well as disturbed flow (d-flow), cause EC activation. In particular, d-flow, which is known to occur in so-called atheroprone areas of large arteries, activates proinflammatory and apoptotic signaling in ECs, leading to EC dysfunction (1,2). A recent genome-wide association study of an independent cohort of patients with various diseases and healthy controls revealed a possible association between the membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1) locus and the severity of several chronic inflammatory diseases, such as inflammatory bowel disease (IBD), psoriasis, and neuroticism (3)(4)(5)(6).…”

Sildenafil (Viagra®) Prevents Cox-1/ TXA2 Pathway-Mediated Vascular Hypercontractility in ApoE-/- Mice

“…In parallel, our laboratories [15, 18, 21-23] and others [24, 25] have published several data supporting the idea that chronic use of sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves endothelial function in the apoE -/- mouse. However, the beneficial effects of this drug on the prostanoid vasoconstrictors and on inflammatory cytokines have not yet been evaluated in this suitable animal model of AT [26, 27]. …”