Mechanotransduction in vascular physiology and atherogenesis

Abstract

Forces that are associated with blood flow are major determinants of vascular morphogenesis and physiology. Blood flow is crucial for blood vessel development during embryogenesis and for regulation of vessel diameter in adult life. It is also a key factor in atherosclerosis, which, despite the systemic nature of major risk factors, occurs mainly in regions of arteries that experience disturbances in fluid flow. Recent data have highlighted the potential endothelial mechanotransducers that might mediate responses to blood flow, the effects of atheroprotective rather than atherogenic flow, the mechanisms that contribute to the progression of the disease and how systemic factors interact with flow patterns to cause atherosclerosis.

Figure 1. Mechanical forces on the vessel wall

A section of an artery wall shows endothelial cells (ECs) that form the inner lining and align longitudinally, and smooth muscle cells (SMCs) that form the outer layers and align circumferentially. Pressure (p) is normal to vessel wall, resulting in circumferential stretch of the vessel wall. Shear stress (τ) is parallel to vessel wall and is exerted longitudinally in the direction of blood flow.

Figure 2. Vascular bifurcation and flow patterns

In straight regions of arteries, the rate of blood flow changes during the cardiac cycle but flow is always in the same direction and patterns are laminar (blue segments). In regions where arteries divide or curve sharply, there are regions where complex flow patterns develop (red segments). Flow in these regions is lower and can reverse direction during the cardiac cycle, so-called oscillatory flow. Endothelial cells (ECs) in regions of high, laminar shear have a quiescent, anti-inflammatory phenotype characterized by alignment in the direction of flow, expression of anti-inflammatory genes, and low levels of oxidative stress, cell turnover and permeability and are protected from atherosclerosis. By contrast, endothelial cells in regions of disturbed shear have an activated, pro-inflammatory phenotype characterized by poor alignment, high turnover, oxidative stress, expression of inflammatory genes and high turnover, associated with high susceptibility to atherosclerosis.

Figure 3. Endothelial mechanotransducers

a | The upper surface of the endothelium has a carbohydrate-rich glycocalyx that extends several hundred microns into the vessel lumen. A fraction of cells in regions of low shear also have a luminal primary cilium several microns long. G protein coupled receptors (GPCRs), heterotrimeric G proteins and ion channels may also reside in the upper plasma membrane. Cells also have ATP channels and/or cell surface ATP synthase. The lateral cell membrane contains the homophilic adhesion receptors platelet-endothelial-cell adhesion molecule-1 (PECAM-1) and VE-cadherin, which bind their counterparts on adjacent cells. Vascular endothelial growth factor (VEGF) receptor (VEGFR) associates laterally with VE-cadherin in these domains. The cortical actin cytoskeleton, actin stress fibers, microtubules and intermediate filaments (not shown) mechanically connect different regions of the cell. Integrin-dependent complexes anchor the cell to the basement membrane. b |. Under fluid shear stress, the glycocalyx experiences drag that is transmitted to the cortical cytoskeleton. The cilium is deflected by flow and bends relative to the apical membrane or cytoskeleton. Both ATP release and its transport [what is the significance of the arrow that points down on the left hand side of ATP synthase? Does it indicate ATP transport?] near the cell surface are modified by flow. Tension is transmitted to the lateral borders and basal membrane where adhesion receptors such a PECAM-1 or integrins experience changes in tension. Changes in fluidity of the apical membrane have been observed and may activate potassium channels, GPCRs or G proteins.

Figure 4. Time course of endothelial activation

Cells under laminar flow (blue line) transiently activate a variety of inflammatory signaling pathways including production of reactive oxygen species (ROS), c-Jun-N-terminal-kinase (JNK), NF-kB, p21-activated kinase (PAK) and expression of a variety of cytokines. However, these are downregulated over times on the order of 1h. Disturbed shear activates the same pathways in a sustained manner. Changes in gene expression that occur over hours to days sustains oxidative stress and the activated phenotype. Alterations in the extracellular matrix (ECM) that occur over days to weeks lead to engagement of integrins that enhance inflammatory pathways. These changes give rise to a persistently activated phenotype that leads to chronic inflammation and vessel remodelling.

Box 1

Box 2