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Vascular smooth muscle

Time-average distribution of the wall shear stress (WSS) in the LIMA–LAD model during one cardiac cycle.
Nordgaard H et al. Cardiovasc Res 2010; 88:512-519 - Click here to view the abstract

Competitive flow from native coronary vessels is a known risk factor for graft failure, which still is an unsolved problem in coronary bypass surgery. By addressing why grafts often fail during competitive flow, essential information with great consequences may be obtained. The upper and lower panels show low and high scale of WSS, respectively. WSS is a determinant of endothelial function. A decrease in WSS may induce endothelial dysfunction, leading to vessel diseases like intimal hyperplasia and atherosclerosis, typical reasons for graft failure. Using computational fluid dynamics, WSS was calculated in three different flow conditions: high competitive flow (due to a non-significant coronary lesion), partial competitive flow (due to a significant coronary lesion), and no competitive flow (totally occluded coronary vessel). High competitive flow was found to produce low and unfavourable WSS (0.3–0.5 Pa), which is consistent with endothelial dysfunction that may impair graft patency in the long term. Partial competitive flow (0.6–3.0 Pa) may be better tolerated as it was found to be similar to the ideal condition of no competitive flow (0.9–3.0 Pa).

Nitrite in pulmonary arterial hypertension: therapeutic avenues in the setting of dysregulated arginine/nitric oxide synthase signalling
Zuckerbraun B S et al. Cardiovasc Res 2011; 89:542-552-Click here to view the abstract

The classic arginine–nitric oxide synthase–nitric oxide pathway. This figure illustrates the ‘classic’ nitric oxide pathway and both cyclic guanosine monophosphate-dependent and -independent signalling. Furthermore, the figure highlights the multiple levels of this pathway that can be taken advantage of for therapeutic benefit. One strategy is to increase nitric oxide synthase substrate availability via l-arginine supplementation or arginase inhibitors. Alternative strategies are to increase nitric oxide synthase enzymes via gene or protein therapy as well as direct deliver of nitric oxide gas via inhalation or pharmacological donors. Additionally, therapeutics take advantage of cyclic guanosine monophosphate-dependent signalling including phosphodiesterase inhibitors, such as sildenafil, and the direct guanylate cyclase activators such as riociguat.

Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans
Michel JB et al. Cardiovasc Res (2011) 90(1): 18-27 doi:10.1093/cvr/cvq337 - Click here to view the abstract

There are now clinical, biological, and radiological data establishing that intraluminal thrombus (ILT) in abdominal aortic aneurysm (AAA) is one of the driving forces of the evolution of dilation toward rupture. ILT is a main source of
1) oxidation, due to the red blood cell (RBC) storage and haem-iron release, and
2) proteolytic activities in AAA, including activation of plasmin and retention of neutrophils, and it is a potential site of weak pathogen contamination.
The pathogenic spatio-temporal role of ILT is directly linked to its permanent renewal at the luminal interface with circulating blood and to the high porosity of this neo-tissue, allowing pressure-dependent outward radial convection of proteases and oxidized molecular mediators towards the arterial wall and the adventitia. Therefore, ILT biology impacts vascular smooth muscle cell disappearance and extracellular matrix degradation in the medial layer of the arterial wall and the angiogenic and adaptive immune responses taking place in the adventitia of AAA.

Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy
Osherov AB et al. Cardiovasc Res (2011) 91(1): 16-26 doi:10.1093/cvr/cvr012 - Click here to view the abstract



Effects of matrix metalloproteinases (MMPs) in the vessel wall.

Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy
Osherov AB et al. Cardiovasc Res (2011) 91(1): 16-26 doi:10.1093/cvr/cvr012 - Click here to view the abstract



Receptor signaling pathways affecting extracellular matrix synthesis in the arterial wall in response to vascular injury. See text for details. Red arrow indicates inhibition, green arrow indicates activation, yellow arrow indicates signal transduction to the nucleus. VSMC, vascular smooth muscle cell. TGF-β, transforming growth factor beta, PDGF, platelet-derived growth factor. MMPs, matrix metalloproteinases, ET, endothelin.

Endothelial cell-borne platelet bridges selectively recruit monocytes in human and mouse models of vascular inflammation
Kuckleburg CJ et al. Cardiovasc Res (2011) 91(1): 134-141 doi:10.1093/cvr/cvr040 - Click here to view the abstract

 

The mechanisms by which secretory SMCs promote the recruitment of monocytes from flowing blood.

The routes by which inflammatory leucocytes are recruited to the artery wall and are enriched within the atherosclerotic environment are poorly described. Here, observations using co-culture and animal models of the diseased artery wall, allied with data from previous studies, show that interactions between cells of the diseased artery wall can generate signals that coordinate the preferential recruitment of monocytes from flowing blood. This process depends upon crosstalk between secretory smooth muscle cells (SMCs) and endothelial cells (ECs), which leads to the plasmin-dependent generation of active transforming growth factor-β1 (TGF-β1). This agent induces von Willebrand factor (vWF) expression on ECs so that platelets are recruited and activated and act as an adhesive bridge between the EC surface and the flowing blood. Monocytes are preferentially recruited from blood by tethering to platelet P-selectin and preferentially activated by CCL2 (MCP-1), which is released from ECs by the action of the platelet chemokine CXCL4 (PF4; platelet factor 4), stimulating the endothelial cell receptor CXCR3b.

This process greatly enriches for monocytes at the EC surface and supports monocyte transmigration. Thus, a series of cellular and molecular interactions initiated by cells resident within the diseased artery are shown to result in the specific recruitment of the predominant population of inflammatory leucocytes recruited during atherogenesis.