Rationale : Shear stress (SS) has an established role in atherosclerotic plaque localization, but how it exerts its protective effect is not fully understood. Objective : To test the hypothesis that SS may downregulate angiotensin type 1 receptors (AT ₁ Rs). Angiotensin II has been shown to be proinflammatory and to promote atherosclerosis. Methods and Results : Using immunohistochemistry, we found a pronounced expression of AT ₁ R in the inner, atheroprone regions of the aortic arch of C57BL/6 and endothelial NO synthase–deficient (eNOS ^−/− ) mice but not eNOS-overexpressing mice. In human umbilical vein endothelial cells (HUVECs), laminar SS (15 dyn/cm ² ) induced a biphasic decrease in AT ₁ R protein expression characterized by a first reduction at 1 hour (31±4% of static control, P <0.01), partial recovery at 3 hours (65±9%), and a second more prolonged decline at 6, 12, and 24 hours (48±9%, 36±9%, 33±5%, respectively, P <0.05). One and 24 hours of SS significantly reduced fluorescent angiotensin binding compared to static HUVECs. Shear-induced downregulation of AT ₁ R was abolished by treatment with protein kinase A and G inhibitors or N ^G -nitro- l -arginine methyl ester (L-NAME). Fittingly, stimulating static HUVECs with an NO donor decreased AT ₁ R protein levels. RT-PCR revealed a significant ( P <0.05) decrease of AT ₁ R mRNA in HUVECs exposed to SS during 3 (6±2% of static control), 6 (4±1%), 12 (4±1%), and 24 hours (15±4%), suggesting a transcriptional downregulation of AT ₁ R at length. Finally, angiotensin-induced vascular cell adhesion molecule was abated in HUVECs exposed to SS and in the outer aortic arch of mice. Conclusions : Our results demonstrate that SS may convey some of its atheroprotective effects through downregulation of AT ₁ R in endothelial cells.

Vascular remodeling associated with increased blood flow involves reactive oxygen species (ROS)-dependent activation of matrix metalloproteinases (MMPs). To investigate the potential role of NF-κB in this process, human umbilical vein endothelial cells were subjected to different flow conditions during a 24-h period. Normal (15 dynes/cm²) and high (30 dynes/cm²) shear stress induced IκBα degradation and NF-κB p65 phosphorylation, and activated MMP-2 and MMP-9. These effects were blunted in cells incubated with the NF-κB inhibitor pyrrolidine dithio-carbamate (PDTC). In mice, creation of a carotid artery–jugular vein arteriovenous fistula (AVF) increased carotid blood flow sixfold, triggering the increase in carotid diameter from 459 ± 8 μm (before AVF) to 531 ± 13 and 669 ± 21 μm (7 and 21 days after AVF). ROS production and NF-κB activity were enhanced in fistulated carotids, but only the latter was blocked by PDTC, although PDTC blocked ROS production in vitro. In PDTC-treated mice, changes in carotid caliber and shear stress matched controls at 7 days, but carotids enlarged only marginally thereafter, reaching only 578 ± 8 μm at 21 days (p < 0.01 vs. untreated). Similarly, both MMP-9 expression and activity were abrogated by PDTC at 3 weeks. Hence, induction of NF-κB by shear stress contributes to MMP induction and allows long-term flow-induced vascular enlargement. Antioxid. Redox Signal. 11, 1641–1649.

Summary: In the developing embryo, the vasculature first takes the form of a web-like network called the vascular plexus. Arterial and venous differentiation is subsequently guided by the specific expression of genes in the endothelial cells that provide spatial and temporal cues for development. Notch1/4, Notch ligand delta-like 4 (Dll4), and Notch downstream effectors are typically expressed in arterial cells along with EphrinB2, whereas chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and EphB4 characterise vein endothelial cells. Haemodynamic forces (blood pressure and blood flow) also contribute importantly to vascular remodelling. Early arteriovenous differentiation and local blood flow may hold the key to future inflammatory diseases. Indeed, despite the fact that atherosclerosis risk factors such as smoking, hypertension, hypercholesterolaemia, and diabetes all induce endothelial cell dysfunction throughout the vasculature, plaques develop only in arteries, and they localise essentially in vessel branch points, curvatures and bifurcations, where blood flow (and consequently shear stress) is low or oscillatory. Arterial segments exposed to high blood flow (and high laminar shear stress) tend to remain plaque-free. These observations have led many to investigate what particular properties of arterial or venous endothelial cells confer susceptibility or protection from plaque formation, and how that might interact with a particular shear stress environment.

Atherosclerosis is the largest contributor toward life-threatening cardiovascular events. Cellular activity and cholesterol accumulation lead to vascular remodeling and the formation of fatty plaques. Complications arise from blood clots, forming at sites of plaque development, which may detach and result in thrombotic occlusions. Vascular smooth muscle cells and macrophages play dominant roles in atherosclerosis. A firm understanding of how these cells influence and modulate each other is pivotal for a better understanding of the disease and the development of novel therapeutics. Recent studies have investigated molecular interactions between both cell types and their impact on disease progression. Here we aim to review the current knowledge. Intercellular communications through soluble factors, physical contact, and extracellular vesicles are discussed. We also present relevant background on scientific methods used to study the disease, the general pathophysiology and intracellular factors involved in phenotypic modulation of vascular smooth muscle cells. We conclude this review with a discussion of the current state, shortcomings and potential future directions of the field.

Nanoparticles are uniquely suited for the study and development of potential therapies against atherosclerosis by virtue of their size, fine-tunable properties, and ability to incorporate therapies and/or imaging modalities. Furthermore, nanoparticles can be specifically targeted to the atherosclerotic plaque, evading off-target effects and/or associated cytotoxicity. There has been a wealth of knowledge available concerning the use of nanotechnologies in cardiovascular disease and atherosclerosis, in particular in animal models, but with a major focus on imaging agents. In fact, roughly 60% of articles from an initial search for this review included examples of imaging applications of nanoparticles. Thus, this review focuses on experimental therapy interventions applied to and observed in animal models. Particular emphasis is placed on how nanoparticle materials and properties allow researchers to learn a great deal about atherosclerosis. The objective of this review was to provide an update for nanoparticle use in imaging and drug delivery studies and to illustrate how nanoparticles can be used for sensing and modelling, for studying fundamental biological mechanisms, and for the delivery of biotherapeutics such as proteins, peptides, nucleic acids, and even cells all with the goal of attenuating atherosclerosis. Furthermore, the various atherosclerosis processes targeted mainly for imaging studies have been summarized in the hopes of inspiring new and exciting targeted therapeutic and/or imaging strategies.

Atherosclerosis progression is a result of chronic and non-resolving inflammation, effective treatments for which still remain to be developed. We designed and developed branched poly(ß-amino ester) nanoparticles (NPs) containing plasmid DNA encoding IL-10, a potent anti-inflammatory cytokine to atherosclerosis. The NPs (NP-VHPK) are functionalized with a targeting peptide (VHPK) specific for VCAM-1, which is overexpressed by endothelial cells at sites of atherosclerotic plaque. The anionic coating affords NP-VHPK with significantly lower toxicity than uncoated NPs in both endothelial cells and red blood cells (RBCs). Following injection of NP-VHPK in ApoE^-/- mice, Cy5-labelled IL-10 significantly accumulates in both whole aortas and aortic sinus sections containing plaque compared to injection with a non-targeted control. Furthermore, IL-10 gene delivery results in an attenuation of inflammation locally at the plaque site. NP-VHPK may thus have the potential to reduce the inflammatory component of atherosclerosis in a safe and effective manner. STATEMENT OF SIGNIFICANCE: Atherosclerosis is a chronic inflammatory disease that results in the formation of lipid-laden plaques within vascular walls. Although treatments using drugs and antibodies are now beginning to address the inflammation in atherosclerosis, neither is sufficient for long-term therapy. In this paper, we introduce a strategy to deliver genes encoding the anti-inflammatory protein interleukin-10 (IL-10) in vivo. We showed that Branched Poly(ß-aminoester) carrying the IL-10 gene are able to localize specifically at the plaque via surface-functionalized targeting moieties against inflamed VCAM-1 and/or ICAM-1 and to facilitate gene transcription by ECs to increase the local concentration of the IL-10 within the plaque. To date, there is no report involving non-viral nanotechnology to provide gene-based therapies for atherosclerosis.