Caveolae: A role in endothelial inflammation and mechanotransduction?

Abstract

Vascular inflammation and disease progression, such as atherosclerosis, are in part a consequence of haemodynamic forces generated by changes in blood flow. The haemodynamic forces, such as shear stress or stretch, interact with vascular endothelial cells, which transduce the mechanical stimuli into biochemical signals via mechanosensors, which can induce an upregulation in pathways involved in inflammatory signaling. However, it is unclear how these mechanosensors respond to shear stress and most significantly what cellular mechanisms are involved in sensing the haemodynamic stimuli. This review explores the transition from shear forces, stretch and pressure to endothelial inflammation and the process of mechanotransduction, specifically highlighting evidence to suggest that caveolae play as a role as mechanosensors. Cardiovascular disease (CVD) is the primary cause of death globally, accounting for over 17 million deaths worldwide in 2008 (WHO, 2013). By 2030, it is predicted that ~25 million people will die annually from cardiovascular-related disorders. Cardiovascular diseases encompass all disease involving heart and blood vessel defects, such as coronary heart disease, myocardial infarction, and cerebrovascular disease (including stroke) as well as a number of other fibrotic disorders. Importantly, increased exposure to CVD risk factors such as smoking, alcohol abuse, physical inactivity, and high cholesterol (hypercholesterolemia) contribute to the growing CVD mortality rates in the western world (WHO, 2013). Of note, elevated blood pressure (BP) or hypertension contributes to more deaths and disease globally than any other risk factor (Forouzanfar et al., 2015). Elevated systolic and/or diastolic blood pressure, resulting from increased systemic vascular resistance or cardiac output, exerts a complex mechanical insult on the arterial wall. Mechanical forces generated at the endothelium in the form of shear stress due to blood flow and stretch caused by blood pressure can potently affect vascular tone resulting in changes in morphology, function, gene expression and the release of vasoactive endothelial autacoids. Several different mechanosensors and multiple signaling pathways have been proposed as regulators of the endothelium's response. There is some evidence that integrins, the cytoskeleton, ion channels, and G proteins may be activated by stretch in vascular smooth muscle cells and that exertion of circumferential stretch on endothelial cells results in increased ICAM-1 (Cheng et al., 1996), VCAM-1 and E-selectin expression (Yun et al., 1999), which are hallmarks of endothelial inflammation. More recently, caveolae, 50-to 100-nm flask-shaped invaginations of the plasma membrane, have also been implicated as mechanosensors. Therefore, it is not surprising that chronic increases in BP have also been shown to result in vascular inflammation where reduced nitric oxide (NO) bioavailability is thought to contribute to endothelial dysfunction, increased reactive oxygen species (ROS) and an upregulation in the production of inflammatory cytokines and chemokines.