1. Introduction

Blood, urine and air are primary examples of biological fluids. Biophysically, fluids can be classified into four basic types: ideal fluid, real fluid, Newtonian fluid and non-Newtonian fluid. Among them, biological fluids are classified only as Newtonian and non-Newtonian. Blood and urine belong to non-Newtonian biofluids since their viscosity is not a constant with respect to the rate of shearing stress; moreover, the removal of the stress causes them to return to their initial viscosity state [1].

ciliopathies or ciliary dysfunctions can lead to a series of disorders such as PKD, hypertension

Sensing Fluid-Shear Stress in the Endothelial System with a Special Emphasis on the Primary Cilium

http://dx.doi.org/10.5772/intechopen.73134

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Physiologically, the primary cilium, a solitary non-motile microtubule-based organelle, protrudes from the surface of mammalian cells [11] into the surrounding tube (vessel/tubule) lumen. Primary cilia work as a chemo- and mechanosensors responding to diverse stimuli,

Since the importance of the primary cilium as a sensor of FSS has been described mainly in the kidney and in the blood vessels, it is worth to describe in brief some aspects of the renal system. During the process of urine formation, the flow of the ultrafiltrate through the proximal tubule (PT) is pulsatile, with variable oscillations due to the heart rate and to tubuloglomerular feedback mechanism mediated by the macula densa. This ultrafiltration mechanism exposes kidney epithelial cells to a constant FSS in a similar way that mimics vascular endothelial cells [14]. Changes in urinary flow through the nephron depend on short-term variations in glomerular filtration rate, tubuloglomerular feedback and fluid absorption along the nephron as well as on long-term factors such as high salt or high protein diet, hypertension and early stages of diabetes [15]. Variations in luminal urinary flow alter the mechanical forces (shear stress, stretch and pressure), which in turn affect epithelial cells in the nephron. Thus, kidney epithelial cells exhibit a highly differentiated brush border composed by microvilli, glycocalyx and primary cilium in order to sense apical shear stress [14]. Tubular flow acts as potent modulator of epithelial kidney cell phenotype by affecting the organization of the cytoskeleton and the brush border, changing cell polarity and modifying various cellular functions such as solute

Recently, several reports showed that an alteration of primary cilia length and function is associated with acute and chronic kidney disease [12, 13, 16–21]. However, the underlying mechanisms behind these associations are still unclear. The main scope of this chapter focuses on the role of primary cilium as one of the multiple mechanotransduction machineries in

In the blood vessels, endothelial cells exhibit cilia that have been involved in blood vessel autoregulation [9], as well as in the pathogenesis of hypertension [9] and atherosclerotic lesions

In this chapter, we will present the physiological role of the endothelial primary cilium as a sensor of FSS. We will make a short review about potential implication of reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and purinergic signaling as modulators of the function of primary cilium. Finally, implication of the primary cilium dysfunction

Primary cilia differ from motile cilia in both structure and function and are usually classified as non-motile organelles, which were first described in 1867 by Alexander Kowalesky in

and atherosclerotic lesions [9].

reabsorption and extracellular matrix remodeling.

sensing FSS in the endothelial vascular and epithelial renal system.

in the kidney and atherosclerotic lesions will be overviewed.

2. Structure of the primary cilium

including FSS [12, 13].

[22, 23].

In order to regulate blood flow, vascular smooth muscle cells (VSMC) induce changes in blood vessel diameter by contraction and relaxation mechanism. Smooth muscle contraction is regulated by central neuronal as well as by local control mechanisms. In particular, the local control, also termed autoregulation, is an important mechanism of vascular tone regulation, maintaining the immediate control of the amount of blood flow within a specific region. Vessel diameter decreases by a sudden increase of transmural pressure and increases by faster flow or high shear stress [2]. Flow shear stress (FSS) is one of the important blood flow-induced hemodynamic forces (Table 1) acting on the blood vessel and is determined by the velocity of blood flow, fluid viscosity and vessel geometry [2–5]. An important determinant of shear stress is the viscosity of blood; shear stress is the energy transferred to the vessel wall due to interaction with a fluid in motion [6]. Shear stress forces are imposed directly to the endothelium and modulate endothelial structure and function through local mechanotransduction mechanisms [5, 7]. FSS is crucial for vascular homeostasis [5].

In a normal homeostatic mechanism and steady laminar shear stress, endothelial cells respond promptly with an increase in the cytosolic calcium (Ca2+), activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production [4, 8] and with the ultimate gene modulation [3, 5, 8]. However, besides laminar flow, oscillatory and turbulent flow patterns are also imposed to the endothelium, which has then to continuously fine-tune its activities as a response [5].

Several structures and processes have been implicated in FSS mechanotransduction into specific biochemical signals, intracellular signaling pathways and gene modulation [5]. Among those structures implicated, the primary cilium emerges as a key sensor of FSS under physiological conditions [9]. Nevertheless, in vascular injury occurring as a result of hypertension for example, normal homeostatic mechanisms are disturbed and vessel wall becomes dysfunctional associated with impaired formation and/or function of primary cilium [5, 10]. Moreover,


Table 1. Various types of hemodynamic forces acting on the blood vessel wall.

ciliopathies or ciliary dysfunctions can lead to a series of disorders such as PKD, hypertension and atherosclerotic lesions [9].

Physiologically, the primary cilium, a solitary non-motile microtubule-based organelle, protrudes from the surface of mammalian cells [11] into the surrounding tube (vessel/tubule) lumen. Primary cilia work as a chemo- and mechanosensors responding to diverse stimuli, including FSS [12, 13].

Since the importance of the primary cilium as a sensor of FSS has been described mainly in the kidney and in the blood vessels, it is worth to describe in brief some aspects of the renal system.

During the process of urine formation, the flow of the ultrafiltrate through the proximal tubule (PT) is pulsatile, with variable oscillations due to the heart rate and to tubuloglomerular feedback mechanism mediated by the macula densa. This ultrafiltration mechanism exposes kidney epithelial cells to a constant FSS in a similar way that mimics vascular endothelial cells [14]. Changes in urinary flow through the nephron depend on short-term variations in glomerular filtration rate, tubuloglomerular feedback and fluid absorption along the nephron as well as on long-term factors such as high salt or high protein diet, hypertension and early stages of diabetes [15]. Variations in luminal urinary flow alter the mechanical forces (shear stress, stretch and pressure), which in turn affect epithelial cells in the nephron. Thus, kidney epithelial cells exhibit a highly differentiated brush border composed by microvilli, glycocalyx and primary cilium in order to sense apical shear stress [14]. Tubular flow acts as potent modulator of epithelial kidney cell phenotype by affecting the organization of the cytoskeleton and the brush border, changing cell polarity and modifying various cellular functions such as solute reabsorption and extracellular matrix remodeling.

Recently, several reports showed that an alteration of primary cilia length and function is associated with acute and chronic kidney disease [12, 13, 16–21]. However, the underlying mechanisms behind these associations are still unclear. The main scope of this chapter focuses on the role of primary cilium as one of the multiple mechanotransduction machineries in sensing FSS in the endothelial vascular and epithelial renal system.

In the blood vessels, endothelial cells exhibit cilia that have been involved in blood vessel autoregulation [9], as well as in the pathogenesis of hypertension [9] and atherosclerotic lesions [22, 23].

In this chapter, we will present the physiological role of the endothelial primary cilium as a sensor of FSS. We will make a short review about potential implication of reactive oxygen species (ROS), vascular endothelial growth factor (VEGF) and purinergic signaling as modulators of the function of primary cilium. Finally, implication of the primary cilium dysfunction in the kidney and atherosclerotic lesions will be overviewed.
