Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis. Laboratory Investigation (2005) 85, 9-23, advance online publication, 29 November 2004; doi:10.1038/labinvest.3700215Keywords: shear stress; atherosclerosis; endothelium; smooth muscle cells; nitric oxide; cytoskeleton; mechanotransductionThe parallel frictional drag force of shear stress is one of the important blood flow-induced mechanical stresses acting on the vessel wall, which also includes the perpendicular force of blood pressure and the cyclic stretch of pulsatile flow. Shear stress is a biomechanical force that is determined by blood flow, vessel geometry and fluid viscosity that is computationally estimated using fluid dynamics models and is expressed in units of dynes/cm 2 .
The study of the cellular and molecular pathogenesis of heart valve disease is an emerging area of research made possible by the availability of cultures of valve interstitial cells (VICs) and valve endothelial cells (VECs) and by the design and use of in vitro and in vivo experimental systems that model elements of valve biological and pathobiological activity. VICs are the most common cells in the valve and are distinct from other mesenchymal cell types in other organs. We present a conceptual approach to the investigation of VICs by focusing on VIC phenotype-function relationships. Our review suggests that there are five identifiable phenotypes of VICs that define the current understanding of their cellular and molecular functions. These include embryonic progenitor endothelial/mesenchymal cells, quiescent VICs (qVICs), activated VICs (aVICs), progenitor VICs (pVICs), and osteoblastic VICs (obVICs). Although these may exhibit plasticity and may convert from one form to another, compartmentalizing VIC function into distinct phenotypes is useful in bringing clarity to our understanding of VIC pathobiology. We present a conceptual model that is useful in the design and interpretation of studies on the function of an important phenotype in disease, the activated VIC. We hope this review will inspire members of the investigative pathology community to consider valve pathobiology as an exciting new frontier exploring pathogenesis and discovering new therapeutic targets in cardiovascular diseases.
Local shear stresses generated by blood flow exert direct mechanical effects on adhesion of circulating leukocytes to vascular endothelium, but their effects on expression of endothelial-leukocyte adhesion molecules have not been determined. Shear stress in rabbit carotid arteries was increased by 170% or decreased by 73% in 5 days by surgical manipulations. En face immunofluorescence staining with the monoclonal antibody Rb1/9 revealed that vascular cell adhesion molecule-1 (VCAM-1) expression was greatly increased under low shear stress, but the distribution of staining was patchy. Thus, 71.4 +/- 7.8% of fields were VCAM-1 positive versus 2.4 +/- 0.47% of fields in control arteries. Frequently, large regions showed consistent but heterogeneous staining. Occasionally, small islands of cells were labeled intensely. Monocytes, detected by use of the monocyte-specific antibody HAM 56, adhered to endothelium under low shear stress; 64.5 +/- 8.2% of the monocytes colocalized with detectable VCAM-1, although many (83.2 +/- 2.8%) VCAM-1-positive regions were devoid of monocytes. VCAM-1 expression also increased significantly but to a lesser extent when shear stress was approximately doubled. Thus, 8.7 +/- 1.5% of fields were VCAM-1 positive under high shear versus 2.5 +/- 0.87% under normal shear stress. No monocytes were detected at high shear stress. At normal shear stresses, intercellular adhesion molecule-1 (ICAM-1), detected by use of the monoclonal antibody Rb2/3, was extensively distributed; thus, 53.5 +/- 5.5% of fields contained ICAM-1-positive cells. The junctional regions of the cells were heavily stained.(ABSTRACT TRUNCATED AT 250 WORDS)
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