Integrating molecular and cellular components of endothelial shear stress mechanotransduction

Abstract

The lining of blood vessels is constantly exposed to mechanical forces exerted by blood flow against the endothelium. Endothelial cells detect these tangential forces (i.e., shear stress), initiating a host of intracellular signaling cascades that regulate vascular physiology. Thus, vascular health is tethered to the endothelial cells' capacity to transduce shear stress. Indeed, the mechanotransduction of shear stress underlies a variety of cardiovascular benefits, including some of those associated with increased physical activity. However, endothelial mechanotransduction is impaired in aging and disease states such as obesity and type 2 diabetes, precipitating the development of vascular disease. Understanding endothelial mechanotransduction of shear stress, and the molecular and cellular mechanisms by which this process becomes defective, is critical for the identification and development of novel therapeutic targets against cardiovascular disease. In this review, we detail the primary mechanosensitive structures that have been implicated in detecting shear stress, including junctional proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1), the extracellular glycocalyx and its components, and ion channels such as piezo1. We delineate which molecules are truly mechanosensitive and which may simply be indispensable for the downstream transmission of force. Furthermore, we discuss how these mechanosensors interact with other cellular structures, such as the cytoskeleton and membrane lipid rafts, which are implicated in translating shear forces to biochemical signals. Based on findings to date, we also seek to integrate these cellular and molecular mechanisms with a view of deciphering endothelial mechanotransduction of shear stress, a tenet of vascular physiology.

Keywords: blood flow; cytoskeleton; endothelium; glycocalyx; mechanosensation.

Figure 1.

The shear stress-induced vascular endothelial growth factor receptor 2 (VEGFR2)/platelet endothelial cell adhesion molecule-1 (PECAM-1)/VE-cadherin endothelial junctional complex. Shear stress causes the translocation of VEGFR2 to the endothelial cell borders to form a junctional complex with PECAM-1 and VE-cadherin. This junctional complex plays a role in mediating mechanotransduction of shear stress-induced prostaglandin I₂ (PGI₂) and nitric oxide (NO) production. Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; PI3K, phosphatidylinositol-3 kinase. Adapted from Martinez-Lemus (36).

Figure 2.

The endothelial glycocalyx transmits force through transmembrane proteoglycans and cell surface receptors to mediate nitric oxide (NO) production. Endothelial proteoglycans and cell surface receptors transduce force detected by the glycocalyx through its interactions with the cytoskeleton and lipid membranes. Many of these proteoglycan or cell surface receptor mechanosensors reside in caveolae and are anchored to the cytoskeleton by proteins such as ankyrin or ezrin/radixin/moesin (ERM). This emphasizes the critical role of the cytoskeleton and caveolae in the mechanotransduction of shear stress to NO production. Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; GPI, glycosylphosphatidylinositol.

Figure 3.

Mechanosensitive ion channels facilitate shear stress-induced increases in intracellular Ca²⁺ and Ca²⁺-sensitive pathways regulating endothelial nitric oxide synthase (eNOS) activity. Shear stress activates piezo1-mediated increases in Ca²⁺ influx and ATP production, which induces sustained transient receptor potential cation channel subfamily V member 4 (TRPV4)-mediated Ca²⁺ influx and purinergic signaling, respectively. Inwardly rectifying potassium channel (Kir) channel increases eNOS activity and may serve as an amplifier for endothelium-derived hyperpolarizing factor (EDHF) vasodilatory signaling. ATP, adenosine triphosphate; Ca²⁺, calcium; CaM, calmodulin; IP₃, Inositol trisphosphate; P2Y₂, purinergic receptor.

Figure 4.

Endothelial mechano-sensors and -transducers cooperate in mechanosensory complexes that detect and transmit forces in cytoskeletal-dependent (force-through-tether) and independent (force-through-lipid) mechanisms. Accumulating evidence suggests that mechanosensors residing in the glycocalyx, such as glypican-1, interact with the cytoskeleton and mediate junctional protein-dependent shear-induced nitric oxide (NO) production. This mechanism may be facilitated by the transmission of force through the cytoskeleton. Furthermore, other glycocalyx mechanosensors of shear stress, such as the hyaluronan-binding CD44 receptor, have been shown to interact with piezo1 to mediate mechanotransduction of shear stress. Akt, protein kinase B; eNOS, endothelial nitric oxide synthase; GPI, glycosylphosphatidylinositol; P2Y₂, purinergic receptor; PECAM-1, platelet and endothelial cell adhesion molecule 1; PGI2, prostaglandin I2 (or prostacyclin); PI3K, phosphatidylinositol-3 kinase; VEGFR2, vascular endothelial growth factor receptor 2; TRPV4, transient receptor potential cation channel subfamily V member 4.